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Department of Biology hosts 2017 Massachusetts Junior Academy of Science Symposium

High school students present research projects to build communication skills while earning membership to the American Junior Academy of Science.

Raleigh McElvery | Department of Biology
October 24, 2017

On Oct. 14, 22 school students from across the state presented their research projects at the annual Massachusetts Junior Academy of Science (MassJAS) Symposium.

The talks were split into two concurrent sessions based on subject: biological and environmental sciences; and engineering, chemistry, mathematics, and physics. Participants were selected based on merit and ranking in this year’s Massachusetts State Science and Engineering Fair.

Judges nominated three students from the biology session and four from physics and engineering as American Junior Academy of Science (AJAS) delegates. Delegates are invited to attend the AJAS Convention, which will be held in Austin, Texas this coming February. The AJAS is a national honor society that meets annually in conjunction with the American Association for the Advancement of Science — the world’s largest science organization and the publisher of Science. All participants were inducted as AJAS fellows.

The sessions took place in adjacent lecture rooms in Building 68. The event was organized by Mandana Sassanfar, director of diversity and science outreach for MIT’s Department of Biology and Department of Brain and Cognitive Sciences, as well as the director of MassJAS. During the event, delegates toured local research institutions, shared their projects with others in the field, and attended conference sessions.

At this year’s MassJAS symposium, the jury for the biological and environmental science session was composed of three graduate students and postdoc from the MIT Department of Biology.

“I really enjoyed hearing how these projects came to be, and what inspired students to ask their respective research questions,” said Sora Kim, a third year graduate student in Tania Baker’s lab and a returning judge. “Some students did these projects at home, while others had collaborations with researchers at local universities. In many cases, these were their first science projects, so being able to understand their own projects and also convey their ideas to a more general audience is really important.”

First-time judge Summer Morrill, a third year graduate student in Angelika Amon’s lab, agreed that learning to present ideas clearly in ways that inspire others is key to the scientific process. “I was excited to hear what people at the high school level think is important in science, because they’re the next generation of scientists,” she said.

Each participant had ten minutes to present, followed by an audience question-and-answer session. The biology-related talks ranged from antimicrobial resistance to gene editing techniques to the effects of wifi router radiation.

Joshua Powers and Natalia Huynh, both juniors at the Everett High School STEM Academy, presented first, describing the results of their summer research project at MIT as part of the LEAH Knox Scholars pilot program. Powers and Huynh pooled their findings, isolating and characterizing bacterial specimens from the Charles River.

“We’re friends and we both go to the same high school, so it was easy to collaborate with both our ideas and our data,” said Powers. “The LEAH Knox Scholars program was intense in that we had the chance to perform more advanced procedures with equipment we’ve never used before in school.”

Huynh also enjoyed tackling larger research questions with more refined tools, adding, “We practiced explaining our results this summer, so today’s presentation was similar to what we’d already done — but a little more intense because it was a competition.”

Nancy Cianchetta, who teaches biotechnology at Everett High School and serves as the coordinator for the STEM Academy, said Powers and Huynh will be part of the very first class to graduate from the Academy. She and many of her students have participated in MIT biology outreach programs over the years.

“I’ve taken my classes here for field trips and career exploration days, and many of my students come for the spring lecture series at the Whitehead Institute,” she said. “The kids get so excited to come to MIT.”

While some participants shared data they’d only just begun to analyze, others had been tackling the same research question for over a year.

Evan Mizerak, a returning MassJAS Symposium winner and senior at Wachusett Regional High School, has spent the past two-and-a-half years collaborating with researchers at the University of Massachusetts Medical School on his project related to heritable infertility in fruit flies.

Mizerak attended last year’s AJAS Convention in Boston, as well as the MIT-sponsored Breakfast with Scientists. This year, delegates met with esteemed faculty, including Institute Professor Phillip Sharp, the winner of the 1993 Nobel Prize in physiology or medicine and a member of the Department of Biology and the Koch Institute for Integrative Cancer Research.

“The AJAS Convention was incredible last year, because we had the chance to meet researchers from around the country — not just in and around Massachusetts,” he said. “At the Breakfast with Scientists, we met with Nobel Prize winners. Being introduced to people I consider celebrities was just amazing.”

“You wouldn’t expect anyone that famous to be interested in our work,” added Emma Kelly, a junior from Newton Country Day School and also a returning presenter. “But these professionals were genuinely curious, and often gave us ideas for new projects and things like that. It was such an incredible opportunity.”

MIT neuroscientists build case for new theory of memory formation

Existence of “silent engrams” suggests that existing models of memory formation should be revised.

Anne Trafton | MIT News Office
October 23, 2017

Learning and memory are generally thought to be composed of three major steps: encoding events into the brain network, storing the encoded information, and later retrieving it for recall.

Two years ago, MIT neuroscientists discovered that under certain types of retrograde amnesia, memories of a particular event could be stored in the brain even though they could not be retrieved through natural recall cues. This phenomenon suggests that existing models of memory formation need to be revised, as the researchers propose in a new paper in which they further detail how these “silent engrams” are formed and re-activated.

The researchers believe their findings offer evidence that memory storage does not rely on the strengthening of connections, or “synapses,” between memory cells, as has long been thought. Instead, a pattern of connections that form between these cells during the first few minutes after an event occurs are sufficient to store a memory.

“One of our main conclusions in this study is that a specific memory is stored in a specific pattern of connectivity between engram cell ensembles that lie along an anatomical pathway. This conclusion is provocative because the dogma has been that a memory is instead stored by synaptic strength,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, the director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, and the study’s senior author.

The researchers also showed that even though memories held by silent engrams cannot be naturally recalled, the memories persist for at least a week and can be “awakened” days later by treating cells with a protein that stimulates synapse formation.

Dheeraj Roy, a recent MIT PhD recipient, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Oct. 23. Other authors are MIT postdoc Shruti Muralidhar and technical associate Lillian Smith.

Silent memories

Neuroscientists have long believed that memories of events are stored when synaptic connections, which allow neurons to communicate with each other, are strengthened. Previous studies have found that if synthesis of certain cellular proteins is blocked in mice immediately after an event occurs, the mice will have no long-term memory of the event.

However, in a 2015 paper, Tonegawa and his colleagues showed for the first time that memories could be stored even when synthesis of the cellular proteins is blocked. They found that while the mice could not recall those memories in response to natural cues, such as being placed in the cage where a fearful event took place, the memories were still there and could be artificially retrieved using a technique known as optogenetics.

The researchers have dubbed these memory cells “silent engrams,” and they have since found that these engrams can also be formed in other situations. In a study of mice with symptoms that mimic early Alzheimer’s disease, the researchers found that while the mice had trouble recalling memories, those memories still existed and could be optogenetically retrieved.

In a more recent study of a process called systems consolidation of memory, the researchers found engrams in the hippocampus and the prefrontal cortex that encoded the same memory. However, the prefrontal cortex engrams were silent for about two weeks after the memory was initially encoded, while the hippocampal engrams were active right away. Over time, the memory in the prefrontal cortex became active, while the hippocampal engram slowly became silent.

In their new PNAS study, the researchers investigated further how these silent engrams are formed, how long they last, and how they can be re-activated.

Similar to their original 2015 study, they trained mice to fear being placed in a certain cage, by delivering a mild foot shock. After this training, the mice freeze when placed back in that cage. As the mice were trained, their memory cells were labeled with a light-sensitive protein that allows the cells to be re-activated with light. The researchers also inhibited the synthesis of cellular proteins immediately after the training occurred.

They found that after the training, the mice did not react when placed back in the cage where the training took place. However, the mice did freeze when the memory cells were activated with laser light while the animals were in a cage that should not have had any fearful associations. These silent memories could be activated by laser light for up to eight days after the original training.

Making connections

The findings offer support for Tonegawa’s new hypothesis that the strengthening of synaptic connections, while necessary for a memory to be initially encoded, is not necessary for its subsequent long-term storage. Instead, he proposes that memories are stored in the specific pattern of connections formed between engram cell ensembles. These connections, which form very rapidly during encoding, are distinct from the synaptic strengthening that occurs later (within a few hours of the event) with the help of protein synthesis.

“What we are saying is that even without new cellular protein synthesis, once a new connection is made, or a pre-existing connection is strengthened during encoding, that new pattern of connections is maintained,” Tonegawa says. “Even if you cannot induce natural memory recall, the memory information is still there.”

This raised a question about the purpose of the post-encoding protein synthesis. Considering that silent engrams are not retrieved by natural cues, the researchers believe the primary purpose of the protein synthesis is to enable natural recall cues to do their job efficiently.

The researchers also tried to reactivate the silent engrams by treating the mice with a protein called PAK1, which promotes the formation of synapses. They found that this treatment, given two days after the original event took place, was enough to grow new synapses between engram cells. A few days after the treatment, mice whose ability to recall the memory had been blocked initially would freeze after being placed in the cage where the training took place. Furthermore, their reaction was just as strong as that of mice whose memories had been formed with no interference.

Sheena Josselyn, an associate professor of psychology and physiology at the University of Toronto, said the findings run counter to the longstanding idea that memory formation involves strengthening of synapses between neurons and that this process requires protein synthesis.

“They showed that a memory formed during protein-synthesis inhibition may be artificially (but not naturally) recalled. That is, the memory is still retained in the brain without protein synthesis, but this memory cannot be accessed under normal conditions, suggesting that spines may not be the key keepers of information,” says Josselyn, who was not involved in the research. “The findings are controversial, but many paradigm-shifting papers are.”

Along with the researchers’ previous findings on silent engrams in early Alzheimer’s disease, this study suggests that re-activating certain synapses could help restore some memory recall function in patients with early stage Alzheimer’s disease, Roy says.

The research was funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.

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
School of Science welcomes new faculty members

This fall brings 14 new professors in the departments of Biology, Chemistry, Mathematics, and Physics.

School of Science
October 10, 2017

This fall, the MIT School of Science has welcomed 14 new professors in the departments of Biology, Chemistry, Mathematics, and Physics.

Ian J. M. Crossfield focuses on the atmospheric characterization of exoplanets through all possible methods — transits, eclipses, phase curves, and direct imaging — from the ground and from space, with an additional interest in the discovery of new exoplanets, especially those whose atmospheres that can be studied in more detail. He joins the MIT Department of Physics as an assistant professor.

Joey Davis, an assistant professor in the Department of Biology, studies the molecular mechanisms underpinning autophagy using biochemical, biophysical, and structural biology techniques such as mass spectrometry and cryo-electron microscopy. This pathway is responsible for protein and organelle degradation and has been linked to a variety of aging associated disorders including neurodegeneration and cancer.

Daniel Harlow works on black holes and cosmology, viewed through the lens of quantum gravity and quantum field theory. He has joined the Department of Physics as assistant professor.

Philip Harris, a new assistant professor in the Department of Physics, searches for dark matter, seeking a deeper understanding of the petabytes of data collected at the Large Hadron Collider. Much of his research exploits new techniques to resolve the structure of quark and gluon decays, known as jet substructure.

Or Hen studies quantum chromodynamics effects in the nuclear medium, and the interplay between partonic and nucleonic degrees of freedom in nuclei, conducting experiments at the Thomas Jefferson and Fermi National Accelerator Laboratories, as well as other accelerators around the world. He has joined the faculty as an assistant professor in the Department of Physics and the Laboratory of Nuclear Science.

Laura Kiessling investigates how carbohydrates are assembled, recognized, and function in living cells, which is crucial to understanding key biological processes such as bacterial cell wall biogenesis, bacteria chemotaxis, enzyme catalysis and inhibition, immunity, and stem cell propagation and differentiation. She is the new Novartis Professor of Chemistry.

Rebecca Lamason investigates how intracellular bacterial pathogens hijack host cell processes to promote infection. In particular, she studies how Rickettsia parkeri and Listeria monocytogenes move through tissues via a process called cell-to-cell spread. She has joined the Department of Biology as an assistant professor.

Sebastian Lourido studies the molecular events that enable parasites in the phylum Apicomplexa to remain widespread and deadly infectious agents. Lourido uses Toxoplasma gondii to model processes conserved throughout the phylum, in order to expand our understanding of eukaryotic diversity and identify specific features that can be targeted to treat parasite infections. He has been welcomed into the Department of Biology as an assistant professor.

Ronald T. Raines, who has joined the faculty as the Firmenich Professor of Chemistry, uses techniques that range from synthetic chemistry to cell biology to illuminate in atomic detail both the chemical basis and the biological purpose for protein structure and protein function. He seeks insights into the relationship between amino-acid sequence and protein function (or dysfunction), as well as to the creation of novel proteins with desirable properties.

Giulia Saccà is an algebraic geometer with a focus on hyperkähler and Calabi-Yau manifolds, K3 surfaces, moduli spaces of sheaves, families of abelian varieties and their degenerations, and symplectic resolutions. She is now an assistant professor in the Department of Mathematics.

Stefani Spranger studies the interactions between cancer and the immune system, with the goal of improving existing immunotherapies or developing novel therapeutic approaches. Spranger seeks to understand how CD8 T cells, otherwise known as killer T cells, are excluded from the tumor microenvironment, with a focus on lung and pancreatic cancers. She has joined the Department of Biology as an assistant professor.

Daniel Suess works at the intersection of inorganic and biological chemistry, studying redox reactions that underpin global biogeochemical cycles, metabolism, and energy conversion. He develops chemical strategies for attaining precise, molecular-level control over the structures of complex active sites. In doing so, his research yields detailed mechanistic insight and enables the preparation of catalysts with improved function. Suess is an assistant professor in the Department of Chemistry.

Wei Zhang is a number theorist who works in arithmetic geometry, with special interest in fundamental objects such as L-functions, which appear in the Riemann hypothesis and its generalizations, and are central to the Langlands program. Zhang has joined the Department of Mathematics as a full professor.

Yufei Zhao, who has joined the Department of Mathematics as an assistant professor, works in combinatorics and graph theory, and is especially interested in problems with extremal, probabilistic, and additive flavors.

Genetic body/brain connection identified in genomic region linked to autism
October 6, 2017

CAMBRIDGE, Mass. – For the first time, Whitehead Institute scientists have documented a direct link between deletions in two genes—fam57ba and doc2a—in zebrafish and certain brain and body traits, such as seizures, hyperactivity, enlarged head size, and obesity.

“Finding the molecular connections between a brain and a body phenotype is indeed really paradigm shifting,” says Whitehead Institute Member Hazel Sive, who is also a professor of biology at MIT. “It lets us think about the common control of these two aspects of phenotype, which is very interesting and could be useful for developing therapies for these phenotypes.”

Both genes reside in the 16p11.2 region of human chromosome 16. About 1 in 2000, or around 4 million people worldwide, have deletions in this region, and these deletions are associated with multiple brain and body symptoms, including autism spectrum disorders, developmental delay, intellectual disability, seizures, and obesity.

Scientists have had difficulty teasing apart the relationship between specific traits and deletions in this region, because it includes at least 25 genes, and because there is not a one-to-one mapping of gene to phenotype. Instead, multiple genes seem to create a web of interactions that produce a variety of characteristics.

To solve such a complex puzzle, Jasmine McCammon, a postdoctoral researcher in Sive’s lab, enlisted the zebrafish as a “living test tube”.  The Sive group uses zebrafish to study the genetic/phenotype connections associated with human disorders. Like the human genome, the zebrafish genome has two copies of each gene, and scientists can remove the function of multiple genes to produce phenotypes that are reminiscent of human symptoms.

The results from McCammon’s initial screen with zebrafish indicate that two genes in the 16p11.2 region could be key for brain development: fam57ba and doc2a. (fam57b encodes a ‘ceramide synthase’ that makes a kind of lipid, and doc2a encodes a regulator of secretion.) McCammon investigated further by deleting one copy of fam57ba and doc2a individually; the effect was minimal. However, simultaneously removing a copy of both genes revealed significant synergy between them. Compared with controls, fish with only one copy of each gene exhibit hyperactivity, increased propensity for seizures, increased body and head size, and fat content. When both copies of only fam57ba are removed, the fish are much larger and with a higher fat content. All of the study’s results are published in the journal Human Molecular Genetics.

Although her findings use zebrafish and are far from the clinic, McCammon was struck by how much people affected by deletions in this genome identified with her results.

“When I spoke with the parents of some kids with neurodevelopmental disorders, I was surprised how much the brain/body connection that we described resonated with them,” she says. “They said that yes, their child has autism, but he also has really weak muscle tone. Or she has a gastrointestinal problem and that’s been more problematic than her behavior issues. For me, it’s been really revealing to talk to people who’ve actually experienced this as opposed to reading about statistics in journals.”

The mechanisms underlying this brain/body connection are still not well understood. One of the identified genes, fam57ba, provides some intriguing hints as to how metabolism and brain function could be intertwined, because it produces an enzyme that plays a role in lipid production and is believed to be a metabolic regulator.  The lipid type, ceramide, also has a functional role in various signaling pathways and affects synaptic function, although its primary role is not in the synapse, but providing structure in cell membranes.

For Sive, the two identified genes could be just the beginning. “Our data suggest that there may be metabolic genes involved in human neurodevelopmental disorders,” she says.  “This is a nascent field, that we’re very interested in going forward.”

This work was supported by Jim and Pat Poitras, Len and Ellen Polaner, and the Markell-Balkin-Weinberg Postdoctoral Fellowship.

Written by Nicole Giese Rura
* * *
Hazel Sive’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a professor of biology at Massachusetts Institute of Technology.
* * *
Full Citation:
“The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes”
Human Molecular Genetics, Volume 26, Issue 19, 1 October 2017.
Jasmine M. McCammon(1), Alicia Blaker-Lee(1), Xiao Chen(2), and Hazel Sive (1,2).
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Department of Biology hosts its first Science Slam

Eight biology trainees had just three minutes to explain their research and earn favor with the judges and audience in new yearly event.

Raleigh McElvery | Department of Biology
October 5, 2017

Nearly 300 spectators crowded into a lecture hall at the Ray and Maria Stata Center on a recent Tuesday to witness the first annual Science Slam, hosted by MIT’s Department of Biology.

A science slam features a series of short presentations where researchers explain their work in a compelling manner and — as the name suggests — make an impact. The presentations aren’t just talks, they’re performances geared towards a science-literate but non-specialized public audience. In this case, competitors were each given one slide and three minutes to tell their scientific tales and earn votes from audience members and judges.

The jury included Ellen Clegg, editorial page editor of The Boston Globe and co-author of two award-winning books, “ChemoBrain” and “The Alzheimer’s Solution;” Emilie Marcus, CEO of Cell Press and editor-in-chief of the flagship journal, Cell; and Ari Daniel, an independent science reporter who produces digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

Among the competitors were five graduate students and three postdocs who hailed from labs scattered throughout Building 68, the Whitehead Institute, the Broad Institute, the Koch Institute for Integrative Cancer Research, and the Picower Institute for Learning and Memory. The storytellers were:

  • Sahin Naqvi, from David Page’s lab, who spoke about the evolution of genetic sex differences in mammals, as well as how these differences impact the likelihood of developing certain diseases based on gender;
  • Sudha Kumari, from Darrell Irvine’s lab, who spoke about her work investigating immune cell interactions — specifically how T cells communicate using physical contact;
  • Deniz Atabay, from Peter Reddien’s lab, who spoke about the ways cells in flatworms self-organize during regeneration to re-form organs, tissues, and even neural circuits;
  • Emma Kowal, from Christopher Burge’s lab, who spoke about her goals to demystify the ways in which certain noncoding regions of genetic sequence, known as introns, contribute to protein production;
  • Xin Tang, from Rudolf Jaenisch’s lab, who spoke about a technique to illuminate the seemingly invisible changes in brain cells that trigger disease, using a glowing enzyme from a firefly;
  • Nicole Aponte, from Troy Littleton’s lab, who spoke about her ability to manipulate brain cell activity in the fruit fly, and study how defects in neuronal connections contribute to developmental disorders;
  • Karthik Shekhar, from Aviv Regev’s lab, who spoke about his efforts to identify and manipulate different types of brain cells, understanding how they assemble into complex networks to facilitate learning, memory, and — in some cases — disease; and
  • Monika Avello, from Alan Grossman’s lab, who spoke about “bacterial sexology,” that is, how and why these organisms choose to block unwanted sexual advances from fellow bacteria.

Vivian Siegel, who oversees the department’s communications efforts, moderated the event. Siegel and the Building 68 communications team joined forces with three members of the Building 68 MIT Postdoctoral Association — Ana Fiszbein, Isabel Nocedal, and Peter Sudmant — to publicize the event and to host two pre-slam workshops, as well as one-on-one training sessions with individual participants.

“Participating in a Science Slam seemed like a great way for our trainees to learn how to communicate to a nonspecialized audience, which is something they will need to be able to do throughout their careers,” Siegel said. “We really wanted to develop a camaraderie among the participants, and bring trainees together from across the department to help each other tell compelling stories about their science.”

Kowal — whose talk was titled “Gone but Not Forgotten: How Do Introns Enhance Gene Expression?”  — ultimately took home both the audience and jury cash prizes. Kowal completed her undergraduate degree in chemical and physical biology at Harvard before coming to MIT for graduate school. Her dream is to write science fiction, so she decided she’d better study science so she’d know what to write about.

“I really enjoyed seeing people get stoked about introns, and the fact that they enhance gene expression,” she said. “It’s a great way to get comfortable explaining your project in a compelling way to a broad audience. Since you’ll probably be telling people about your work for a while, I think it’s a very good use of time to practice doing that.”

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.