Research Area: Cancer Biology

Stuck on the membrane

A pro-metastatic transcription factor’s journey from anonymity to a promising target for breast cancer therapy

October 20, 2017

An overwhelming majority of deaths from cancer are associated not with the primary tumor, but instead with its metastases to other sites in the body. For this reason, understanding the properties of cancer cells that give them a high metastatic potential, and identifying molecular strategies to intervene, is critical for improving clinical outcomes.

One of the hallmarks of cancer cells with high metastatic potential is an epithelial to mesenchymal transition (EMT). This shift in their gene expression landscape is a harbinger for both invasive behavior and anti-cancer drug resistance. One signaling pathway active in cells that have undergone EMT transition, the PERK pathway, has been of particular interest to Whitehead Institute Member and Massachusetts Institute of Technology associate professor of biology Piyush Gupta and postdoctoral researchers in Gupta’s lab, Yu-Xiong Feng and Dexter Jin. The PERK signaling pathway has been a sought-after target for a number of types of cancer, including breast cancer. Drug companies had largely given up on the PERK signaling pathway as a target, however, because when it is inhibited, it also has the unintended consequence of affecting glucose regulation to the degree that mice given PERK inhibitors typically develop diabetes within a few weeks. Gupta and colleagues hypothesized that downstream elements of the pathway could include targets with more specific effects on metastatic behavior, potentially enabling the development of therapies that do not result in the unintended consequences associated with inhibiting PERK. 

In a recent article in Nature Communications, Gupta, Feng, Jin, and colleagues describe CREB3L1, a factor downstream of the PERK pathway that is active in the subset of triple negative breast cancer cells and tumor cells that have undergone an EMT transition. CREB3L1 expression is associated with distant metastasis and is important for the transformed cell’s invasive and drug resistant properties. While factors like CREB3L1, called transcription factors, are usually difficult to target with small molecules, Gupta and his team zeroed in on a unique property it shares with only a small handful of other factors-it is normally stuck to the membrane of a cellular compartment called the endoplasmic reticulum and, in order for it to be active, it need to be cut free by factors called proteases. Gupta and colleagues show that certain protease inhibitors can actually stop the activation of CREB3L1 in its tracks, along with the invasive and drug resistance properties its activation confers. 

While the PERK signaling pathway has been an attractive target for anticancer therapy, its more general cellular role made it an intractable target. The downstream factor of the pathway  CREB3L1 is a potential new target for breast cancer therapy whose specificity of action makes it an attractive option for targeting metastatic behavior.

By Lisa Girard
Citation:
Feng Y-X, Jin DX, et al. “Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1.” Nature Communications DOI:10.1038/s41467-017-01052-y
New target for treating “undruggable” lung cancer

Drug already in clinical trials may be effective on some aggressive adenocarcinomas.

Becky Ham | MIT News correspondent
October 2, 2017

Mutations in the KEAP1 gene could point the way to treating an aggressive form of lung cancer that is driven by “undruggable” mutations in the KRAS gene, according to a new study by MIT researchers.

KEAP1 mutations occur alongside KRAS mutations in about 17 percent of lung adenocarcinoma cases. Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and co-senior author of the study, and his colleagues found that cancer cells with nonfunctioning KEAP1 genes are hungry for glutamine, an amino acid essential for protein synthesis and energy use. Starving these cells of glutamine may thus offer a way to treat cancers with both KRAS and KEAP1 mutations.

Indeed, small-molecule-based inhibitors of glutaminase, an enzyme crucial to glutamine metabolism, slowed cancer cell growth and led to smaller tumors overall in human lung adenocarcinoma cell lines and in tumors in mice with KEAP1 mutations, the researchers found.

The study offers a way to identify lung cancer patients who might respond well to drugs that block the work of glutaminase, says MIT graduate student Rodrigo Romero, a first author on the paper that appears in the Oct. 2 online edition of Nature Medicine.

“All cell lines that we have currently tested that are KEAP1-mutant — independent of their KRAS status — appear to be exquisitely sensitive to glutaminase inhibitors,” says Romero, a graduate student in Jacks’ lab, who participated in the MIT Summer Research Program (MSRP) as an undergraduate.

Hyperactivating the antioxidant response

Lung adenocarcinoma accounts for about 40 percent of U.S. lung cancers, and 15 to 30 percent of those cases contain a KRAS mutation. KRAS has been “notoriously difficult to inhibit” because the usual ways of blocking the KRAS protein’s interactions or interfering with the protein’s targets have fallen short, says Romero.

Lung cancers containing KRAS mutations often harbor other mutations, including KEAP1, which is the third most frequently mutated gene in lung adenocarcinoma. To find out more about how these co-mutations affect lung cancer progression, the MIT research team created KEAP1 mutations in mouse models of lung adenocarcinoma, using the CRISPR/Cas9 gene-editing system to target the gene.

The KEAP1 protein normally represses another protein called NRF2, which controls the activation of an antioxidant response that removes toxic, reactive oxygen species from cells. When the researchers disabled KEAP1 with loss-of-function mutations, NRF2 was able to accumulate and contribute to a “hyperactivation” of the antioxidant response.

Lung adenocarcinomas bearing the KEAP1 mutation may “take advantage of this [hyper-activation] to promote cellular growth or detoxify intracellular damaging agents,” Romero says.

In fact, when the researchers examined genes targeted by NRF2 across a sample of human lung adenocarcinoma tumors, they concluded that the expression of these genes was greater in advanced stage IV tumors, and that patients with such “up-regulated” NRF2 tumors had significantly worse survival rates than other lung adenocarcinoma patients.

Tumors hungry for glutamine

Romero and colleagues used CRISPR/Cas9 to learn more about other genetic interactions with KEAP1 mutants. Their screening demonstrated that lung cancer cells with KRAS and KEAP1 loss-of function mutations were more dependent than other cells on increased amounts of glutamine.

To learn whether this glutamine hunger could be a therapeutic vulnerability, the researchers tested two glutaminase inhibitors against the cancer cells, including one compound called CB-839 that is in phase I clinical trials for KRAS-mutant lung cancer. CB-839 slowed growth and kept tumors smaller than normal in lung adenocarcinoma with KEAP1 mutations, the researchers found.

Phase I clinical trials that treat KEAP1-mutant lung adenocarcinoma patients with a combination of CB-839 and the cancer immunotherapy drug nivolumab (Opdivo) are also underway, says Romero, who notes the MIT study might help identify patients who would be good candidates for these trials.

“There are also many clinical trials testing the efficacy of glutaminase inhibition in a variety of cancer types, independent of KRAS status. However, the results from these studies are still unclear,” Romero says.

Jacks emphasizes that his laboratory has and will continue to study several mutations beyond KEAP1 that may cooperate with KRAS in their mouse models of human lung adenocarcinoma. “The complexity of human cancer can be quite daunting,” he notes. “The genetic tools that we have assembled allow us to create models of many individual subtypes of the disease and in this way begin to define the exploitable vulnerabilities of each. The observed sensitivity of KEAP1 mutant tumors to glutaminase inhibitors is an important example of this approach. There will be more.”

Co-authors on the Nature Medicine paper include former Koch Institute postdoc Thales Papagiannakopoulos, now at New York University, and MIT professor of biology Matthew Vander Heiden. The research was funded by the Laura and Isaac Perlmutter Cancer Support Grant, the National Institutes of Health, and the Koch Institute Support Grant from the National Cancer Institute.

Biologists identify possible new strategy for halting brain tumors

Cutting off a process that cancerous cells rely on can force them to stop growing.

Anne Trafton | MIT News Office
September 28, 2017

MIT biologists have discovered a fundamental mechanism that helps brain tumors called glioblastomas grow aggressively. After blocking this mechanism in mice, the researchers were able to halt tumor growth.

The researchers also identified a genetic marker that could be used to predict which patients would most likely benefit from this type of treatment. Glioblastoma is usually treated with radiation and the chemotherapy drug temozolamide, which may extend patients’ lifespans but in most cases do not offer a cure.

“There are very few specific or targeted inhibitors that are used in the treatment of brain cancer. There’s really a dire need for new therapies and new ideas,” says Michael Hemann, an associate professor of biology at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and a senior author of the study.

Drugs that block a key protein involved in the newly discovered process already exist, and at least one is in clinical trials to treat cancer. However, most of these inhibitors do not cross the blood-brain barrier, which separates the brain from circulating blood and prevents large molecules from entering the brain. The MIT team hopes to develop drugs that can cross this barrier, possibly by packaging them into nanoparticles.

The study, which appears in Cancer Cell on Sept. 28, is a collaboration between the labs of Hemann; Jacqueline Lees, associate director of the Koch Institute and the Virginia and D.K. Ludwig Professor for Cancer Research; and Phillip Sharp, an MIT Institute Professor and member of the Koch Institute. The paper’s lead authors are former MIT postdoc Christian Braun, recent PhD recipient Monica Stanciu, and research scientist Paul Boutz.

Too much splicing

Several years ago, Stanciu and Braun came up with the idea to use a type of screen known as shRNA to seek genes involved in glioblastoma. This test involves using short strands of RNA to block the expression of specific genes. Using this approach, researchers can turn off thousands of different genes, one per tumor cell, and then measure the effects on cell survival.

One of the top hits from this screen was the gene for a protein called PRMT5. When this gene was turned off, tumor cells stopped growing. Previous studies had linked high levels of PRMT5 to cancer, but the protein is an enzyme that can act on hundreds of other proteins, so scientists weren’t sure exactly how it was stimulating cancer cell growth.

Further experiments in which the researchers analyzed other genes affected when PRMT5 was inhibited led them to hypothesize that PRMT5 was using a special type of gene splicing to stimulate tumor growth. Gene splicing is required to snip out portions of messenger RNA known as introns, that are not needed after the gene is copied into mRNA.

In 2015, Boutz and others in Sharp’s lab discovered that about 10 to 15 percent of human mRNA strands still have one to three “detained introns,” even though they are otherwise mature. Because of those introns, these mRNA molecules can’t leave the nucleus.

“What we think is that these strands are basically an mRNA reservoir. You have these unproductive isoforms sitting in the nucleus, and the only thing that keeps them from being translated is that one intron,” says Braun, who is now a physician-scientist at Ludwig Maximilian University of Munich.

In the new study, the researchers discovered that PRMT5 plays a key role in regulating this type of splicing. They speculate that neural stem cells utilize high levels of PRMT5 to guarantee efficient splicing and therefore expression of proliferation genes. “As the cells move toward their mature state, PRMT5 levels drop, detained intron levels rise, and those messenger RNAs associated with proliferation get stuck in the nucleus,” Lees says.

When brain cells become cancerous, PRMT5 levels are typically boosted and the splicing of proliferation-associated mRNA is improved, ultimately helping the cells to grow uncontrollably.

Predicting success

When the researchers blocked PRMT5 in tumor cells, they found that the cells stopped dividing and entered a dormant, nondividing state. PRMT5 inhibitors also halted growth of glioblastoma tumors implanted under the skin of mice, but they did not work as well in tumors located in the brain, because of the difficulties in crossing the blood-brain barrier.

Unlike many existing cancer treatments, the PRMT5 inhibitors did not appear to cause major side effects. The researchers believe this may be because mature cells are not as dependent as cancer cells on PRMT5 function.

The findings shed light on why researchers have previously found PRMT5 to be a promising potential target for cancer treatment, says Omar Abdel-Wahab, an assistant member in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, who was not involved in the study.

“PRMT5 has a lot of roles, and until now, it has not been clear what is the pathway that is really important for its contributions to cancer,” says Abdel-Wahab. “What they have found is that one of the key contributions is in this RNA splicing mechanism, and furthermore, when RNA splicing is disrupted, that key pathway is disabled.”

The researchers also discovered a biomarker that could help identify patients who would be most likely to benefit from a PRMT5 inhibitor. This marker is a ratio of two proteins that act as co-factors for PRMT5’s splicing activity, and reveals whether PRMT5 in those tumor cells is involved in splicing or some other cell function.

“This becomes really important when you think about clinical trials, because if 50 percent or 25 percent of tumors are going to have some response and the others are not, you may not have a way to target it toward those patients that may have a particular benefit. The overall success of the trial may be damaged by lack of understanding of who’s going to respond,” Hemann says.

The MIT team is now looking into the potential role of PRMT5 in other types of cancer, including lung tumors. They also hope to identify other genes and proteins involved in the splicing process they discovered, which could also make good drug targets.

Spearheaded by students and postdocs from several different labs, this project offers a prime example of the spirit of collaboration and “scientific entrepreneurship” found at MIT and the Koch Institute, the researchers say.

“I think it really is a classic example of how MIT is a sort of bottom-up place,” Lees says. “Students and postdocs get excited about different ideas, and they sit in on each other’s seminars and hear interesting things and pull them together. It really is an amazing example of the creativity that young people at MIT have. They’re fearless.”

The research was funded by the Ludwig Center for Molecular Oncology at MIT, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the National Institutes of Health, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Three MIT biologists receive NIH Outstanding Investigator Awards

Graham Walker, Michael Yaffe, and Robert Weinberg earn support from the National Institutes of Health to further their research endeavors.

Raleigh McElvery | Department of Biology
September 19, 2017

This fall, two faculty members from the MIT Department of Biology received R35 Outstanding Investigator Awards sponsored by the National Institute of Environmental Health Sciences (NIEHS), while a third garnered the same distinction from the National Cancer Institute (NCI). These awards provide long-term support to experienced investigators with outstanding records of research productivity as they undertake lengthy projects with unusual potential.

Graham Walker, the American Cancer Society Professor in the Department of Biology at MIT, a member of the Center for Environmental Health Sciences, and affiliate member of the Koch Institute for Integrative Cancer Research, is one of two biology faculty to earn the R35 Outstanding Investigator Award from the NIEHS.

This award is supported by the NIEHS through the Revolutionizing Innovative, Visionary Environmental health Research (RIVER) program. The program recognizes outstanding investigators in the field of environmental health, potentially offering up to $750,000 per year over the next eight years.

The awardees include both mid-career and senior researchers, whose work spans many aspects environmental health science — including technology development, mechanistic, clinical, and epidemiological research. A total of eight investigators received the NIEHS RIVER R35 this year.

“The RIVER program is designed to fund people, not projects,” said David Balshaw, chief of the NIEHS Exposure, Response, and Technology Branch who leads the NIEHS team overseeing this initiative. “It gives outstanding environmental health scientists stable funding, time, and, importantly, flexibility to pursue creative scientific ideas, rather than constantly writing grants to support their research programs.”

Walker will use his award to continue investigating the fundamental mechanisms of mutagenesis and DNA repair, with a special emphasis on the Rev1/3/7-dependent pathway of mutagenic translation synthesis found in eukaryotes, including humans. He and his colleagues recently published evidence suggesting that inhibiting this pathway could potentially improve chemotherapy.

Michael Yaffe, the David H. Koch Professor of Science at MIT, a member of the Koch Institute and the Center for Environmental Health Sciences, and attending surgeon at the Beth Israel Deaconess Medical Center, also received a NIEHS RIVER R35 award.

Yaffe’s work concerns how cells respond to injury, including damage to DNA and RNA molecules arising because of the environment and in response to drugs used to treat cancer. He is also interested in the relationship between inflammation, blood clotting, and cancer. He employs multidisciplinary approaches harnessing techniques from biochemistry, structural and cell biology, computer science, and systems biology/engineering.

Yaffe will use his funds to further a project investigating the roles of protein kinases in coordinating cellular responses to damage to both DNA and RNA molecules.

Robert Weinberg, founding member of the Whitehead Institute, professor of biology at MIT, an affiliate member of the Koch Institute, and director of the MIT Ludwig Center for Molecular Oncology, has received his R35 Outstanding Investigator Award from the NCI.

The award provides up to $600,000 per year over seven years to accomplished cancer researchers, nominated by their institutions, who have served as principal investigators on an NCI grant for the last five years. A total of 18 investigators received the NCI Outstanding Investigator Award this year.

“The NCI Outstanding Investigator Award addresses a problem that many cancer researchers experience: finding a balance between focusing on their science while ensuring that they will have funds to continue their research in the future,” said Dinah Singer, director of NCI’s Division of Cancer Biology. “With seven years of uninterrupted funding, NCI is providing investigators the opportunity to fully develop exceptional and ambitious cancer research programs.”

Weinberg is a pioneer in cancer research, best known for his role in discovering the first human oncogene — a gene that, when activated, can spur tumor growth. His lab is also credited with isolating the first known tumor suppressor gene.

He will use his funds to delve into the mechanisms of metastasis — the process that allows cancer cells to spread. He aims to learn more about how these cells disseminate from primary tumors, as well as how they become established in distant tissues after they metastasize.

Department of Biology welcomes three new faculty members

Recent additions bring diverse expertise and cultural perspectives to research community.

Raleigh McElvery | Department of Biology
July 25, 2017

On July 1, MIT Department of Biology welcomed three new faculty members. Since they were all born outside the continental U.S., these newcomers add to the diversity of cultural experiences and contribute to the global face of science at MIT and its affiliated institutions around Kendall Square. The triad also enhances the department’s diverse array of research initiatives. Their interests are as far-reaching as their roots, and range from investigating genetic diseases and cancer immunotherapy to exploiting parasite vulnerabilities.

“When creative individuals with distinct perspectives and approaches come together in an innovative environment like MIT, the possibilities for scientific collaboration and accomplishment are exceptional,” says Alan Grossman, head of the department. “I couldn’t be more pleased to welcome three such outstanding and accomplished individuals into our research community.”

Eliezer Calo

Eliezer Calo is no stranger to MIT. Although he grew up on a farm more than a thousand miles away in the mountains of Carolina, Puerto Rico, Calo first set foot in MIT’s Building 68 11 years ago — and hasn’t wavered in his decision to become a biologist since. In 2006, as part of the MIT Summer Research Program (MSRP), Calo spent 10 weeks studying under Professor Stephen Bell, examining DNA replication. At the time, Calo was a chemistry major at the University of Puerto Rico, but returned post-graduation to MIT’s Department of Biology, earning his PhD while serving as both a teaching assistant for MIT’s course 7.01 (Introduction to Biology) and MSRP program assistant.

“MIT is very unique,” he says. “I’ve done research at multiple institutions, and yet nothing quite compares. Here, the impossible is made possible.”

After completing his postdoctoral training at Stanford University, Calo returned to Cambridge, Massachusetts, this past January as an assistant professor and extramural member at the Koch Institute to head his own lab — exploring the ways in which errors in cellular organelles called ribosomes can lead to disease.

Ribosomes are vital to the translation of genetic code into the molecules integral to life, but are far less often acknowledged for their role in embryonic development. Calo suggests that when ribosomes are not constructed correctly, they are unable to carry out their cellular duties, hindering cell growth and causing developmental disorders. Calo is interested in one condition specifically: Treacher Collins syndrome, which stems from a mutation in a single gene that impedes proper ribosomal assembly. He will soon transfer his experiments from cell cultures to a new model system — zebrafish — in order to further unravel the relationship between ribosome structure and disease.

“The research I do now is purely based on my interest in understanding how cells work,” Calo says. “Specifically, how the mechanisms controlling growth and proliferation operate. These are essential processes that led to the emergence of multicellular organisms, and thus to our own existence.”

Stefani Spranger

One building over in MIT’s Koch Institute, newly-appointed Assistant Professor Stefani Spranger will work to harness the body’s own defense force to pinpoint and eradicate cancer. Spranger carried her passion for immunotherapy across seas from Munich, Germany. As the daughter of two engineers, Spranger was raised on science. “My parents fostered my curiosity,” she says, “which led to my initial motivation to go into science: to figure out how things work.”

While earning her bachelor’s and master’s degrees from the Ludwig-Maximilians University of Munich, Spranger discussed publications focusing on two clinical trials that used engineered immune cells to combat malignant melanoma. These publications ignited Spranger’s enthusiasm for immune-based therapies, which in turn spurred her doctoral and postdoctoral training at the Helmholtz-Zentrum Munich in the Institute for Molecular Immunology and the University of Chicago, respectively.

While Spranger’s education helped hone her immunology research skills, she is excited to experience a more varied academic environment encompassing a range of disciplines. “I was drawn to MIT because of its diverse faculty and the breadth of research interests,” she says.

Spranger’s lab will employ tumor models in mice to determine how cancer and immune cells interact. In particular, she aims to discern the many factors related to the cells, tissues, and environment that could affect the immune system’s anti-tumor response. Ultimately, Spranger hopes to contribute to new treatments that trigger the body’s defense to thwart cancer.

Sebastian Lourido

Trained as both an artist and a scientist, Sebastian Lourido works to counter an entirely different kind of invader spreading biological mayhem: parasites. Originally from Colombia, he was recently named assistant professor of biology, joining the cohort of 15 faculty members at the Whitehead Institute for Biomedical Research — one of just 28 individuals to ever receive this appointment. The title may be new, but this is familiar turf for Lourido. He became a Whitehead Fellow in 2012, after receiving his PhD in microbiology from Washington University in St. Louis and a bachelor’s in studio art and cell and molecular biology from Tulane University. A pioneer in more ways than one, Lourido formed his own lab as a fellow rather than following a more conventional postdoc path.

Lourido spent much of his childhood exploring his mother’s genetics lab, where he analyzed practically anything he could fit under a microscope. “That experience solidified my excitement for the invisible mechanisms that make up the living world,” he says. “I can’t remember a time when I didn’t know that genetic information was carried in our cells in the form of DNA, and passed from one generation to the next.”

Constantly seeking ways to merge his artistic endeavors with scientific ones, Lourido leverages his creativity to glean insight into the systems and structures that constitute life.  He probes a group of microscopic invaders known as Apicomplexan parasites, revealing their weaknesses in order to devise potential treatments. Lourido’s team was the first to perform a genome-wide functional analysis of an apicomplexan — gaining deeper understanding of the genes and molecules key for the invasion process. In 2013, Lourido received the National Institutes of Health (NIH) Director’s Early Independence Award, and with it a five-year grant to investigate motility in one kind of parasite, Toxoplasma gondii. This same interloper is also the subject of Lourido’s two-year NIH-funded project, for which he is the principal investigator.

Lourido has found the MIT community both welcoming and inclusive. Even as he was interviewing for his new position, he was struck by the collaborative, collegial, and nurturing environment.

“This level of engagement permeates the other elements of our community — students, postdocs, and staff scientists — who drive the exciting research happening every day at MIT,” he says. “There are many forces that shape the diversity of our campus, and we need to be vigilant and work hard to continue to encourage and support scientists from different backgrounds, experiences, and cultures.”

School of Science professors granted tenure

Seven award-winning faculty members represent the departments of Physics, Chemistry, and Biology.

Bendta Schroeder | School of Science
June 28, 2017

The School of Science has announced that seven of its faculty members have been granted tenure by MIT.

This year’s newly-tenured professors are:

Mircea Dincă, associate professor in the Department of Chemistry, addresses research challenges related to the storage and consumption of energy and global environmental concerns through the synthesis and characterization of new inorganic and organic materials. His work has applications in heterogeneous catalysis, energy conversion and storage, chemical sensing, gas separation, and water-based technologies including adsorption heat pumps and water production and purification. By designing and synthesizing new materials, Dincă aims to learn more about fundamental processes such as electron and ion transport through ordered solids, the reactivity and electrochemistry of low-coordinate metal ions in porous crystals, the effects of conformational changes on the electronic properties of molecules, and the behavior of materials at the interface with solid-state devices.

Dincă earned a BS in chemistry at Princeton University and a PhD in inorganic chemistry at the University of California at Berkeley. Following a postdoc appointment at MIT in the Department of Chemistry, he joined its faculty in 2010. Among Dincă’s awards and honors are an Alfred P. Sloan Research Fellowship, a Camille Dreyfus Teacher-Scholar Award, and the Alan T. Waterman Award

Liang Fu, the Lawrence C. (1944) and Sarah W. Biedenharn Career Development Assistant Professor in the Department of Physics, is interested in novel topological phases of matter and their experimental realizations. He works on the theory of topological insulators and topological superconductors, with a focus on predicting and proposing their material realizations and experimental signatures. He is also interested in potential applications of topological materials, ranging from tunable electronics and spintronics, to quantum computation.

Fu obtained a BS in physics from the University of Science and Technology of China and a PhD in physics from the University of Pennsylvania. Following an appointment as a Junior Fellow at Harvard University, he joined the MIT faculty in 2012. Fu is the recipient of a Packard Fellowship for Science and Engineering and the New Horizons in Physics Prize.

Jeff Gore, associate professor in the Department of Physics, uses experimentally-tractable microcosms such as bacterial communities to explore the physics of complex living systems, examining how interactions between individuals drives the evolution and ecology of communities. Gore’s primary areas of research include the behavior of populations near tipping points that lead to collapse, the evolution of cooperative behaviors within a species or community, and the determining factors for multi-species diversity within a community.

Gore received a BS in physics, mathematics, economics, and electrical engineering from MIT and a PhD in physics from the University of California at Berkeley. He returned to MIT as a Pappalardo Postdoctoral Fellow in the Department of Physics and subsequently joined the faculty in 2010. Gore’s awards and honors include an Allen Distinguished Investigator Award, an NIH Director’s New Innovator Award, and a National Science Foundtion CAREER Award.

Jeremiah Johnson, the Firmenich Career Development Associate Professor in the Department of Chemistry, designs macromolecules and their syntheses to address problems in chemistry, medicine, biology, energy, and polymer physics. Johnson works with a range of materials and applications, including nano-scale, brush-arm star polymer architectures for in vivo drug delivery, imaging, and self-assembly; hydrogels for the analysis of how molecular network defects impact mechanics; and polymers for surface functionalization and energy storage.

Johnson completed a BS in biomedical engineering and chemistry at Washington University in St. Louis and a PhD in chemistry at Columbia University. Following an appointment as a Beckman Institute Postdoctoral Scholar at the Caltech, Johnson joined the MIT faculty in 2011. Johnson is the recipient of several awards including an Alfred P. Sloan Research Fellowship and a 3M Non-Tenured Faculty Award.

Brad Pentelute, the Pfizer-Laubach Career Development Associate Professor in the Department of Chemistry, modifies naturally occurring proteins to enhance their therapeutic properties for human medicine, focusing on the use of cysteine arylation to generate abiotic macromolecular proteins, the precision delivery of biomolecules into cells, and the development of fast flow platforms to rapidly produce polypeptides.

Pentelute earned a BS in chemistry and a BA in psychology at the University of Southern California, followed by a PhD in organic chemistry at the University of Chicago. After a postdoc fellowship at Harvard Medical School, Pentelute joined the MIT faculty in 2011. His awards and honors include an Alfred P. Sloan Research Fellowship, a Novartis Early Career Award, and an Amgen Young Investigator Award.

Jesse Thaler, associate professor of physics and member of the Laboratory for Nuclear Science, is a theoretical particle physicist whose research focus is the Large Hadron Collider (LHC) experiment at CERN. Thaler aims to maximize the discovery potential of the LHC by applying theoretical insights from quantum field theory. He is particularly interested in novel methods to test the properties of dark matter at the LHC and beyond, as well as the theoretical structures and experimental signatures of supersymmetry. Thaler also develops new methods to characterize jets, which are collimated sprays of particles that are copiously produced at the LHC. These techniques exploit the substructure of jets to enhance the search for new physics as well as to illuminate the structure of the standard model itself.

Thaler received his PhD in physics from Harvard University and his BS in mathematics and physics from Brown University. After a fellowship at the Miller Institute for Basic Research in Science at the University of California at Berkeley, he joined the MIT faculty in the Department of Physics in 2010. His awards and honors include an Early Career Research Award from the U.S. Department of Energy, a Presidential Early Career Award for Scientists and Engineers from the White House, an Alfred P. Sloan Research Fellowship, and an MIT Harold E. Edgerton Faculty Achievement Award.

Matthew Vander Heiden is the Eisen and Chang Career Development Associate Professor in the Department of Biology. His laboratory is studying how mammalian cell metabolism is adapted to support function, with a particular focus on the role metabolism plays in cancer. He uses mouse models to study how changes in metabolism impact all aspects of cancer progression with a goal of finding novel ways to exploit altered metabolism to help patients.

Vander Heiden earned a BS, an MD, and a PhD from the University of Chicago, and completed his clinical training in internal medicine and medical oncology at the Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. After postdoctoral research at Harvard Medical School, Vander Heiden joined the faculty of the MIT Department of Biology and the Koch Institute in 2010. Among Vander Heiden’s awards and honors include a Burroughs Wellcome Fund Career Award for Medical Sciences, a Damon Runyon-Rachleff Innovation Award, a Stand Up To Cancer Innovative Research Grant, and being named a Howard Hughes Medical Institute Faculty Scholar.

How cells combat chromosome imbalance

Biologists discover the immune system can eliminate cells with too many or too few chromosomes.

Anne Trafton | MIT News Office
June 19, 2017

Most living cells have a defined number of chromosomes: Human cells, for example, have 23 pairs. As cells divide, they can make errors that lead to a gain or loss of chromosomes, which is usually very harmful.

For the first time, MIT biologists have now identified a mechanism that the immune system uses to eliminate these genetically imbalanced cells from the body. Almost immediately after gaining or losing chromosomes, cells send out signals that recruit immune cells called natural killer cells, which destroy the abnormal cells.

The findings raise the possibility of harnessing this system to kill cancer cells, which nearly always have too many or too few chromosomes.

“If we can re-activate this immune recognition system, that would be a really good way of getting rid of cancer cells,” says Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in MIT’s Department of Biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

Stefano Santaguida, a research scientist at the Koch Institute, is the lead author of the paper, which appears in the June 19 issue of Developmental Cell.

“A downward spiral”

Before a cell divides, its chromosomes replicate and then line up in the middle of the cell. As the cell divides into two daughter cells, half of the chromosomes are pulled into each cell. If these chromosomes fail to separate properly, the process leads to an imbalanced number of chromosomes in the daughter cells — a state known as aneuploidy.

When aneuploidy occurs in embryonic cells, it is almost always fatal to the organism. For human embryos, extra copies of any chromosome are lethal, with the exceptions of chromosome 21, which produces Down syndrome; chromosomes 13 and 18, which lead to developmental disorders known as Patau and Edwards syndromes; and the X and Y sex chromosomes, extra copies of which may cause various disorders but are not usually lethal.

In recent years, Amon’s lab has been exploring an apparent paradox of aneuploidy: When normal adult cells become aneuploid, it impairs their ability to survive and proliferate; however, cancer cells, which are nearly all aneuploid, can grow uncontrollably.

“Aneuploidy is highly detrimental in most cells. However, aneuploidy is highly associated with cancer, which is characterized by upregulated growth. So, a very important question is: If aneuploidy hampers cell proliferation, why are the vast majority of tumors aneuploid?” Santaguida says.

To try to answer that question, the researchers wanted to find out more about how aneuploidy affects cells. Over the past few years, Santaguida and Amon have been studying what happens to cells immediately after they experience a mis-segregation of chromosomes, leading to imbalanced daughter cells.

In the new study, they investigated the effects of this imbalance on the cell division cycle by interfering with the process of proper chromosome attachment to the spindle, the structure that holds chromosomes in place at the cell’s equator before division. This interference leads some chromosomes to lag behind and get shuffled into the two daughter cells.

The researchers found that after the cells underwent their first division, in which some of the chromosomes were unevenly distributed, they soon initiated another cell division, which produced even more chromosome imbalance, as well as significant DNA damage. Eventually, the cells stopped dividing altogether.

“These cells are in a downward spiral where they start out with a little bit of genomic mess, and it just gets worse and worse,” Amon says.

“This paper very convincingly and clearly shows that when chromosomes are lost or gained, initially cells can’t tell if their chromosomes have mis-segregated,” says David Pellman, a professor of pediatric oncology at Dana-Farber Cancer Institute who was not involved in the study. “Instead, the imbalance of chromosomes leads to cellular defects and an imbalance of proteins and genes that can significantly disrupt DNA replication and cause further damage to the chromosomes.”

Targeting aneuploidy

As genetic errors accumulate, aneuploid cells eventually become too unstable to keep dividing. In this senescent state, they start producing inflammation-inducing molecules such as cytokines. When the researchers exposed these cells to immune cells called natural killer cells, the natural killer cells destroyed most of the aneuploid cells.

“For the first time, we are witnessing a mechanism that might provide a clearance of cells with imbalanced chromosome numbers,” Santaguida says.

In future studies, the researchers hope to determine more precisely how aneuploid cells attract natural killer cells, and to find out whether other immune cells are involved in clearing aneuploid cells. They would also like to figure out how tumor cells are able to evade this immune clearance, and whether it may be possible to restart the process in patients with cancer, since about 90 percent of solid tumors and 75 percent of blood cancers are aneuploid.

“At some point, cancer cells, which are highly aneuploid, are able to evade this immune surveillance,” Amon says. “We have really no understanding of how that works. If we can figure this out, that probably has tremendous therapeutic implications, given the fact that virtually all cancers are aneuploid.”

The research was funded, in part, by the National Institutes of Health, the Kathy and Curt Marble Cancer Research Fund, the American Italian Cancer Foundation, a Fellowship in Cancer Research from Marie Curie Actions, the Italian Association for Cancer Research, and a Koch Institute Quinquennial Cancer Research Fellowship.

Biologists identify key step in lung cancer evolution

Blocking the transition to a more aggressive state could offer a new treatment strategy.

Anne Trafton | MIT News Office
May 10, 2017

Lung adenocarcinoma, an aggressive form of cancer that accounts for about 40 percent of U.S. lung cancer cases, is believed to arise from benign tumors known as adenomas.

MIT biologists have now identified a major switch that occurs as adenomas transition to adenocarcinomas in a mouse model of lung cancer. They’ve also discovered that blocking this switch prevents the tumors from becoming more aggressive. Drugs that interfere with this switch may thus be useful in treating early-stage lung cancers, the researchers say.

“Understanding the molecular pathways that get activated as a tumor transitions from a benign state to a malignant one has important implications for treatment. These findings also suggests methods to prevent or interfere with the onset of advanced disease,” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the study’s senior author.

The switch occurs when a small percentage of cells in the tumor begin acting like stem cells, allowing them to give rise to unlimited populations of new cancer cells.

“It seems that the stem cells are the engine of tumor growth. They’re endowed with very robust proliferative potential, and they give rise to other cancer cells and also to more stem-like cells,” says Tuomas Tammela, a postdoc at the Koch Institute and lead author of the paper, which appears in the May 10 online edition of Nature.

Tumor stem cells

In this study, the researchers focused on the role of a cell signaling pathway known as Wnt. This pathway is usually turned on only during embryonic development, but it is also active in small populations of adult stem cells that can regenerate specific tissues such as the lining of the intestine.

One of the Wnt pathway’s major roles is maintaining cells in a stem-cell-like state, so the MIT team suspected that Wnt might be involved in the rapid proliferation that occurs when early-stage tumors become adenocarcinomas.

The researchers explored this question in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma. In these mice, they found that Wnt signaling is not active in adenomas, but during the transition, about 5 to 10 percent of the tumor cells turn on the Wnt pathway. These cells then act as an endless pool of new cancer cells.

In addition, about 30 to 40 percent of the tumor cells begin to produce chemical signals that create a “niche,” a local environment that is necessary to maintain cells in a stem-cell-like state.

“If you take a stem cell out of that microenvironment, it rapidly loses its properties of stem-ness,” Tammela says. “You have one cell type that forms the niche, and then you have another cell type that’s receiving the niche cues and behaves like a stem cell.”

While Wnt has been found to drive tumor formation in some other cancers, including colon cancer, this study points to a new kind of role for it in lung cancer and possibly other cancers such as pancreatic cancer.

“What’s new about this finding is that the pathway is not a driver, but it modifies the characteristics of the cancer cells. It qualitatively changes the way cancer cells behave,” Tammela says.

“It’s a very nice paper that points to the influence of the microenvironment in tumor growth and shows that the microenvironment includes factors secreted by a subset of tumor cells,” says Frederic de Sauvage, vice president for molecular oncology research at Genentech, who was not involved in the study.

Targeting Wnt

When the researchers gave the mice a drug that interferes with Wnt proteins, they found that the tumors stopped growing, and the mice lived 50 percent longer. Furthermore, when these treated tumor cells were implanted into another animal, they failed to generate new tumors.

The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the tumors showed Wnt activation and 80 percent had niche cells that stimulate Wnt activity. These findings suggest it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients, the researchers say.

They are also working on ways to deliver Wnt inhibitors in a more targeted fashion, to avoid some of the side effects caused by the drugs. Another possible way to avoid side effects may be to develop more specific inhibitors that target only the Wnt proteins that are active in lung adenocarcinomas. The Wnt inhibitor that the researchers used in this study, which is now in clinical trials to treat other types of cancer, targets all 19 of the Wnt proteins.

The research was funded by the Janssen Pharmaceuticals-Koch Institute Transcend Program, the Lung Cancer Research Foundation, the Howard Hughes Medical Institute, and the Cancer Center Support grant from the National Cancer Institute.

New model could speed up colon cancer research

Introducing genetic mutations with CRISPR offers a fast and accurate way to simulate the disease.

Anne Trafton | MIT News Office
May 1, 2017

Using the gene-editing system known as CRISPR, MIT researchers have shown in mice that they can generate colon tumors that very closely resemble human tumors. This advance should help scientists learn more about how the disease progresses and allow them to test new therapies.

Once formed, many of these experimental tumors spread to the liver, just like human colon cancers often do. These metastases are the most common cause of death from colon cancer.

“That’s been a missing piece in the study of colon cancer. There is really no reliable method for recapitulating the metastatic progression from a primary tumor in the colon to the liver,” says Omer Yilmaz, an MIT assistant professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the lead senior author of the study, which appears in the May 1 issue of Nature Biotechnology.

The study builds on recent work by Tyler Jacks, the director of the Koch Institute, who has also used CRISPR to generate lung and liver tumors in mice.

“CRISPR-based technologies have begun to revolutionize many aspects of cancer research, including building mouse models of the disease with greater speed and greater precision. This study is a good example of both,” says Jacks, who is also an author of the Nature Biotechnology paper.

The paper’s lead authors are Jatin Roper, a research affiliate at the Koch Institute and a gastroenterologist at Tufts Medical Center, and Tuomas Tammela, a research scientist at the Koch Institute.

Mimicking human tumors

For many years, cancer biologists have taken two distinct approaches to modeling cancer. One is to grow immortalized human cancer cells known as cancer cell lines in a lab dish. “We’ve learned a lot by studying these two-dimensional cell lines, but they have limitations,” Yilmaz says. “They don’t really reproduce the complex in vivo environment of a tumor.”

Another widely used technique is genetically engineering mice with mutations that predispose them to develop cancer. However, it can take years to breed such mice, especially if they have more than one cancer-linked mutation.

Recently, researchers have begun using CRISPR to generate cancer models. CRISPR, originally discovered by biologists studying the bacterial immune system, consists of a DNA-cutting enzyme called Cas9 and short RNA guide strands that target specific sequences of the genome, telling Cas9 where to make its cuts. Using this process, scientists can make targeted mutations in the genomes of living animals, either deleting genes or inserting new ones.

To induce cancer mutations, the investigators package the genes for Cas9 and the RNA guide strand into viruses called lentiviruses, which are then injected into the target organs of adult mice.

Yilmaz, who studies colon cancer and how it is influenced by genes, diet, and aging, decided to adapt this approach to generate colon tumors in mice. He and members of his lab were already working on a technique for growing miniature tissues known as organoids — three-dimensional growths that, in this case, accurately replicate the structure of the colon.

In the new paper, the researchers used CRISPR to introduce cancer-causing mutations into the organoids and then delivered them via colonoscopy to the colon, where they attached to the lining and formed tumors.

“We were able to transplant these 3-D mini-intestinal tumors into the colon of recipient mice and recapitulate many aspects of human disease,” Yilmaz says.

More accurate modeling

Once the tumors are established in the mice, the researchers can introduce additional mutations at any time, allowing them to study the influence of each mutation on tumor initiation, progression, and metastasis.

Almost 30 years ago, scientists discovered that colon tumors in humans usually acquire cancerous mutations in a particular order, but they haven’t been able to accurately model this in mice until now.

“In human patients, mutations never occur all at once,” Tammela says. “Mutations are acquired over time as the tumor progresses and becomes more aggressive, more invasive, and more metastatic. Now we can model this in mice.”

To demonstrate that ability, the MIT team delivered organoids with a mutated form of the APC gene, which is the cancer-initiating mutation in 80 percent of colon cancer patients. Once the tumors were established, they introduced a mutated form of KRAS, which is commonly found in colon and many other cancers.

The scientists also delivered components of the CRISPR system directly into the colon wall to quickly model colon cancer by editing the APC gene. They then added CRISPR components to also edit the gene for P53, which is commonly mutated in colon and other cancers.

“These new approaches reduce the time frame to develop genetically engineered mice from two years to just a few months, and involve very basic gene engineering with CRISPR,” Roper says. “We used P53 and KRAS to demonstrate the principle that the CRISPR editing approach and the organoid transplantation approach can be used to very quickly model any possible cancer-associated gene.”

In this study, the researchers also showed that they could grow tumor cells from patients into organoids that could be transplanted into mice. This could give doctors a way to perform “personalized medicine” in which they test various treatment options against a patient’s own tumor cells.

Fernando Camargo, a professor of stem cell and regenerative biology at Harvard University, says the study represents an important advance in colon cancer research.

“It allows investigators to have a very flexible model to look at multiple aspects of colorectal cancer, from basic biology of the genes involved in progression and metastasis, to testing potential drugs,” says Camargo, who was not involved in the research.

Yilmaz’ lab is now using these techniques to study how other factors such as metabolism, diet, and aging affect colon cancer development. The researchers are also using this approach to test potential new colon cancer drugs.

The research was funded by the Howard Hughes Medical Institute, the National Institutes of Health, the Department of Defense, the V Foundation V Scholar Award, the Sidney Kimmel Scholar Award, the Pew-Stewart Trust Scholar Award, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the American Federation of Aging Research, and the Hope Funds for Cancer Research.