Research Area: Cancer Biology

Gene-editing technique could speed up study of cancer mutations

With the new method, scientists can explore many cancer mutations whose roles are unknown, helping them develop new drugs that target those mutations.

Anne Trafton | MIT News Office
May 11, 2023

Genomic studies of cancer patients have revealed thousands of mutations linked to tumor development. However, for the vast majority of those mutations, researchers are unsure of how they contribute to cancer because there’s no easy way to study them in animal models.

In an advance that could help scientists make a dent in that long list of unexplored mutations, MIT researchers have developed a way to easily engineer specific cancer-linked mutations into mouse models.

Using this technique, which is based on CRISPR genome-editing technology, the researchers have created models of several different mutations of the cancer-causing gene Kras, in different organs. They believe this technique could also be used for nearly any other type of cancer mutation that has been identified.

Such models could help researchers identify and test new drugs that target these mutations.

“This is a remarkably powerful tool for examining the effects of essentially any mutation of interest in an intact animal, and in a fraction of the time required for earlier methods,” says Tyler Jacks, the David H. Koch Professor of Biology, a member of the Koch Institute for Integrative Cancer Research at MIT, and one of the senior authors of the new study.

Francisco Sánchez-Rivera, an assistant professor of biology at MIT and member of the Koch Institute, and David Liu, a professor in the Harvard University Department of Chemistry and Chemical Biology and a core institute member of the Broad Institute, are also senior authors of the study, which appears today in Nature Biotechnology.

Zack Ely PhD ’22, a former MIT graduate student who is now a visiting scientist at MIT, and MIT graduate student Nicolas Mathey-Andrews are the lead authors of the paper.

Faster editing

Testing cancer drugs in mouse models is an important step in determining whether they are safe and effective enough to go into human clinical trials. Over the past 20 years, researchers have used genetic engineering to create mouse models by deleting tumor suppressor genes or activating cancer-promoting genes. However, this approach is labor-intensive and requires several months or even years to produce and analyze mice with a single cancer-linked mutation.

“A graduate student can build a whole PhD around building a model for one mutation,” Ely says. “With traditional models, it would take the field decades to catch up to all of the mutations we’ve discovered with the Cancer Genome Atlas.”

In the mid-2010s, researchers began exploring the possibility of using the CRISPR genome-editing system to make cancerous mutations more easily. Some of this work occurred in Jacks’ lab, where Sánchez-Rivera (then an MIT graduate student) and his colleagues showed that they could use CRISPR to quickly and easily knock out genes that are often lost in tumors. However, while this approach makes it easy to knock out genes, it doesn’t lend itself to inserting new mutations into a gene because it relies on the cell’s DNA repair mechanisms, which tend to introduce errors.

Inspired by research from Liu’s lab at the Broad Institute, the MIT team wanted to come up with a way to perform more precise gene-editing that would allow them to make very targeted mutations to either oncogenes (genes that drive cancer) or tumor suppressors.

In 2019, Liu and colleagues reported a new version of CRISPR genome-editing called prime editing. Unlike the original version of CRISPR, which uses an enzyme called Cas9 to create double-stranded breaks in DNA, prime editing uses a modified enzyme called Cas9 nickase, which is fused to another enzyme called reverse transcriptase. This fusion enzyme cuts only one strand of the DNA helix, which avoids introducing double-stranded DNA breaks that can lead to errors when the cell repairs the DNA.

The MIT researchers designed their new mouse models by engineering the gene for the prime editor enzyme into the germline cells of the mice, which means that it will be present in every cell of the organism. The encoded prime editor enzyme allows cells to copy an RNA sequence into DNA that is incorporated into the genome. However, the prime editor gene remains silent until activated by the delivery of a specific protein called Cre recombinase.

Since the prime editing system is installed in the mouse genome, researchers can initiate tumor growth by injecting Cre recombinase into the tissue where they want a cancer mutation to be expressed, along with a guide RNA that directs Cas9 nickase to make a specific edit in the cells’ genome. The RNA guide can be designed to induce single DNA base substitutions, deletions, or additions in a specified gene, allowing the researchers to create any cancer mutation they wish.

Modeling mutations

To demonstrate the potential of this technique, the researchers engineered several different mutations into the Kras gene, which drives about 30 percent of all human cancers, including nearly all pancreatic adenocarcinomas. However, not all Kras mutations are identical. Many Kras mutations occur at a location known as G12, where the amino acid glycine is found, and depending on the mutation, this glycine can be converted into one of several different amino acids.

The researchers developed models of four different types of Kras mutations found in lung cancer: G12C, G12D, G12R, and G12A. To their surprise, they found that the tumors generated in each of these models had very different traits. For example, G12R mutations produced large, aggressive lung tumors, while G12A tumors were smaller and progressed more slowly.

Learning more about how these mutations affect tumor development differently could help researchers develop drugs that target each of the different mutations. Currently, there are only two FDA-approved drugs that target Kras mutations, and they are both specific to the G12C mutation, which accounts for about 30 percent of the Kras mutations seen in lung cancer.

The researchers also used their technique to create pancreatic organoids with several different types of mutations in the tumor suppressor gene p53, and they are now developing mouse models of these mutations. They are also working on generating models of additional Kras mutations, along with other mutations that help to confer resistance to Kras inhibitors.

“One thing that we’re excited about is looking at combinations of mutations including Kras mutations that drives tumorigenesis, along with resistance associated mutations,” Mathey-Andrews says. “We hope that will give us a handle on not just whether the mutation causes resistance, but what does a resistant tumor look like?”

The researchers have made mice with the prime editing system engineered into their genome available through a repository at the Jackson Laboratory, and they hope that other labs will begin to use this technique for their own studies of cancer mutations.

The research was funded by the Ludwig Center at MIT, the National Cancer Institute, a Howard Hughes Medical Institute Hanna Grey Fellowship, the V Foundation for Cancer Research, a Koch Institute Frontier Award, the MIT Research Support Committee, a Helen Hay Whitney Postdoctoral Fellowship, the David H. Koch Graduate Fellowship Fund, the National Institutes of Health, and the Lustgarten Foundation for Pancreatic Cancer Research.

Other authors of the paper include Santiago Naranjo, Samuel Gould, Kim Mercer, Gregory Newby, Christina Cabana, William Rideout, Grissel Cervantes Jaramillo, Jennifer Khirallah, Katie Holland, Peyton Randolph, William Freed-Pastor, Jessie Davis, Zachary Kulstad, Peter Westcott, Lin Lin, Andrew Anzalone, Brendan Horton, Nimisha Pattada, Sean-Luc Shanahan, Zhongfeng Ye, Stefani Spranger, and Qiaobing Xu.

Why lung cancer doesn’t respond well to immunotherapy

A new study reveals that lymph nodes near the lungs create an environment that weakens T-cell responses to tumors.

Anne Trafton | MIT News Office
February 2, 2023

Immunotherapy — drug treatment that stimulates the immune system to attack tumors — works well against some types of cancer, but it has shown mixed success against lung cancer.

A new study from MIT helps to shed light on why the immune system mounts such a lackluster response to lung cancer, even after treatment with immunotherapy drugs. In a study of mice, the researchers found that bacteria naturally found in the lungs help to create an environment that suppresses T-cell activation in the lymph nodes near the lungs.

The researchers did not find that kind of immune-suppressive environment in lymph nodes near tumors growing near the skin of mice. They hope that their findings could help lead to the development of new ways to rev up the immune response to lung tumors.

“There is a functional difference between the T-cell responses that are mounted in the different lymph nodes. We’re hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung-tumor-targeting T cells,” says Stefani Spranger, the Howard S. and Linda B. Stern Career Development Assistant Professor of Biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.

MIT graduate student Maria Zagorulya is the lead author of the paper, which appears today in the journal Immunity.

Failure to attack

For many years, scientists have known that cancer cells can send out immunosuppressive signals, which leads to a phenomenon known as T-cell exhaustion. The goal of cancer immunotherapy is to rejuvenate those T cells so they can begin attacking tumors again.

One type of drug commonly used for immunotherapy involves checkpoint inhibitors, which remove the brakes on exhausted T cells and help reactivate them. This approach has worked well with cancers such as melanoma, but not as well with lung cancer.

Spranger’s recent work has offered one possible explanation for this: She found that some T cells stop working even before they reach a tumor, because of a failure to become activated early in their development. In a 2021 paper, she identified populations of dysfunctional T cells that can be distinguished from normal T cells by a pattern of gene expression that prevents them from attacking cancer cells when they enter a tumor.

“Despite the fact that these T cells are proliferating, and they’re infiltrating the tumor, they were never licensed to kill,” Spranger says.

In the new study, her team delved further into this activation failure, which occurs in the lymph nodes, which filter fluids that drain from nearby tissues. The lymph nodes are where “killer T cells” encounter dendritic cells, which present antigens (tumor proteins) and help to activate the T cells.

To explore why some killer T cells fail to be properly activated, Spranger’s team studied mice that had tumors implanted either in the lungs or in the flank. All of the tumors were genetically identical.

The researchers found that T cells in lymph nodes that drain from the lung tumors did encounter dendritic cells and recognize the tumor antigens displayed by those cells. However, these T cells failed to become fully activated, as a result of inhibition by another population of T cells called regulatory T cells.

These regulatory T cells became strongly activated in lymph nodes that drain from the lungs, but not in lymph nodes near tumors located in the flank, the researchers found. Regulatory T cells are normally responsible for making sure that the immune system doesn’t attack the body’s own cells. However, the researchers found that these T cells also interfere with dendritic cells’ ability to activate killer T cells that target lung tumors.

The researchers also discovered how these regulatory T cells suppress dendritic cells: by removing stimulatory proteins from the surface of dendritic cells, which prevents them from being able to turn on killer-T-cell activity.

Microbial influence

Further studies revealed that the activation of regulatory T cells is driven by high levels of interferon gamma in the lymph nodes that drain from the lungs. This signaling molecule is produced in response to the presence of commensal bacterial — bacteria that normally live in the lungs without causing infection.

The researchers have not yet identified the types of bacteria that induce this response or the cells that produce the interferon gamma, but they showed that when they treated mice with an antibody that blocks interferon gamma, they could restore killer T cells’ activity.

Interferon gamma has a variety of effects on immune signaling, and blocking it can dampen the overall immune response against a tumor, so using it to stimulate killer T cells would not be a good strategy to use in patients, Spranger says. Her lab is now exploring other ways to help stimulate the killer T cell response, such as inhibiting the regulatory T cells that suppress the killer-T-cell response or blocking the signals from the commensal bacteria, once the researchers identify them.

The research was funded by a Pew-Stewart Scholarship, the Koch Institute Frontier Research program, the Ludwig Center at the Koch Institute, and an MIT School of Science Fellowship in Cancer Research.

Enzyme “atlas” helps researchers decipher cellular pathways

Biologists have mapped out more than 300 protein kinases and their targets, which they hope could yield new leads for cancer drugs.

Anne Trafton | MIT News Office
January 11, 2023

One of the most important classes of human enzymes are protein kinases — signaling molecules that regulate nearly all cellular activities, including growth, cell division, and metabolism. Dysfunction in these cellular pathways can lead to a variety of diseases, particularly cancer.

Identifying the protein kinases involved in cellular dysfunction and cancer development could yield many new drug targets, but for the vast majority of these kinases, scientists don’t have a clear picture of which cellular pathways they are involved in, or what their substrates are.

“We have a lot of sequencing data for cancer genomes, but what we’re missing is the large-scale study of signaling pathway and protein kinase activation states in cancer. If we had that information, we would have a much better idea of how to drug particular tumors,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.

Yaffe and other researchers have now created a comprehensive atlas of more than 300 of the protein kinases found in human cells, and identified which proteins they likely target and control. This information could help scientists decipher many cellular signaling pathways, and help them to discover what happens to those pathways when cells become cancerous or are treated with specific drugs.

Lewis Cantley, a professor of cell biology at Harvard Medical School and Dana Farber Cancer Institute, and Benjamin Turk, an associate professor of pharmacology at Yale School of Medicine, are also senior authors of the paper, which appears today in Nature. The paper’s lead authors are Jared Johnson, an instructor in pharmacology at Weill Cornell Medical College, and Tomer Yaron, a graduate student at Weill Cornell Medical College.

“A Rosetta stone”

The human genome includes more than 500 protein kinases, which activate or deactivate other proteins by tagging them with a chemical modification known as a phosphate group. For most of these kinases, the proteins they target are unknown, although research into kinases such as MEK and RAF, which are both involved in cellular pathways that control growth, has led to new cancer drugs that inhibit those kinases.

To identify additional pathways that are dysregulated in cancer cells, researchers rely on phosphoproteomics using mass spectrometry — a technique that separates molecules based on their mass and charge — to discover proteins that are more highly phosphorylated in cancer cells or healthy cells. However, until now, there has been no easy way to interrogate the mass spectrometry data to determine which protein kinases are responsible for phosphorylating those proteins. Because of that, it has remained unknown how those proteins are regulated or misregulated in disease.

“For most of the phosphopeptides that are measured, we don’t know where they fit in a signaling pathway. We don’t have a Rosetta stone that you could use to look at these peptides and say, this is the pathway that the data is telling us about,” Yaffe says. “The reason for this is that for most protein kinases, we don’t know what their substrates are.”

Twenty-five years ago, while a postdoc in Cantley’s lab, Yaffe began studying the role of protein kinases in signaling pathways. Turk joined the lab shortly after, and the three have since spent decades studying these enzymes in their own research groups.

“This is a collaboration that began when Ben and I were in Lew’s lab 25 years ago, and now it’s all finally really coming together, driven in large part by what the lead authors, Jared and Tomer, did,” Yaffe says.

In this study, the researchers analyzed two classes of kinases — serine kinases and threonine kinases, which make up about 85 percent of the protein kinases in the human body — based on what type of structural motif they put phosphate groups onto.

Working with a library of peptides that Cantley and Turk had previously created to search for motifs that kinases interact with, the researchers measured how the peptides interacted with all 303 of the known serine and threonine kinases. Using a computational model to analyze the interactions they observed, the researchers were able to identify the kinases capable of phosphorylating every one of the 90,000 known phosphorylation sites that have been reported in human cells, for those two classes of kinases.

To their surprise, the researchers found that many kinases with very different amino acid sequences have evolved to bind and phosphorylate the same motifs on their substrates. They also showed that about half of the kinases they studied target one of three major classes of motifs, while the remaining half are specific to one of about a dozen smaller classes.

Decoding networks

This new kinase atlas can help researchers identify signaling pathways that differ between normal and cancerous cells, or between treated and untreated cancer cells, Yaffe says.

“This atlas of kinase motifs now lets us decode signaling networks,” he says. “We can look at all those phosphorylated peptides, and we can map them back onto a specific kinase.”

To demonstrate this approach, the researchers analyzed cells treated with an anticancer drug that inhibits a kinase called Plk1, which regulates cell division. When they analyzed the expression of phosphorylated proteins, they found that many of those affected were controlled by Plk1, as they expected. To their surprise, they also discovered that this treatment increased the activity of two kinases that are involved in the cellular response to DNA damage.

Yaffe’s lab is now interested in using this atlas to try to find other dysfunctional signaling pathways that drive cancer development, particularly in certain types of cancer for which no genetic drivers have been found.

“We can now use phosphoproteomics to say, maybe in this patient’s tumor, these pathways are upregulated or these pathways are downregulated,” he says. “It’s likely to identify signaling pathways that drive cancer in conditions where it isn’t obvious what the genetics that drives the cancer are.”

The research was funded by the Leukemia and Lymphoma Society, the National Institutes of Health, Cancer Research UK, the Brain Tumour Charity, the Charles and Marjorie Holloway foundation, the MIT Center for Precision Cancer Medicine, and the Koch Institute Support (core) grant from the National Cancer Institute.

The molecules behind metastasis
Greta Friar | Whitehead Institute
January 4, 2023

Many cancer cells never leave their original tumors. Some cancer cells evolve the ability to migrate to other tissues, but once there cannot manage to form new tumors, and so remain dormant. The deadliest cancer cells are those that can not only migrate to, but also thrive and multiply in distant tissues. These metastatic cancer cells are responsible for most of the deaths associated with cancer. Understanding what enables some cancer cells to metastasize—to spread and form new tumors—is an important goal for researchers, as it will help them develop therapies to prevent or reverse those deadly occurrences.

Past research from Whitehead Institute Member Robert Weinberg and others suggests that cancer cells are best able to form metastatic tumors when the cells are in a particular state called the quasi-mesenchymal (qM) state. New research from Weinberg and Arthur Lambert, once a postdoc in Weinberg’s lab and now an associate director of translational medicine at AstraZeneca, has identified two gene-regulating molecules as important for keeping cancer cells in the qM state. The research, published in the journal Developmental Cell on December 19, shows that these molecules, ΔNp63 and p73, enable breast cancer cells to form new tumors in mice, and illuminates important aspects of how they do so.

Most potent in the middle

Cells enter the qM state by undergoing the epithelial-mesenchymal transition (EMT), a developmental process that can be co-opted by cancer cells. In the EMT, cells transition from an epithelial state through a spectrum of more mesenchymal states, which allows them to become more mobile and aggressive. Cells in the qM state have only transitioned partway through the EMT, becoming more, but not fully, mesenchymal. This middle ground is perfect for metastasis, whereas cells on either end of the spectrum—cells that are excessively epithelial or excessively mesenchymal—lose their metastatic abilities.

Lambert and colleagues wanted to understand more about how cancer stem cells, which can seed metastases and recurrent tumors, remain in a metastasis-prone qM state. They analyzed how gene activity was regulated in those cells and identified two transcription factors—molecules that influence the activity of target genes—as important. One of the transcription factors, ΔNp63, appeared to most directly control cancer stem cells’ ability to maintain a qM state. The other molecule, p73, seemed to have a similar role because it can activate ΔNp63. When either transcription factor was inactivated, the cancer stem cells transitioned to the far end of the EMT spectrum and so were unable to metastasize.

Next, the researchers looked at what genes ΔNp63 regulates in cancer stem cells. They expected to find a pattern of gene regulation resembling what they would see in healthy breast stem cells. Instead they found a pattern closely resembling what one would see in cells involved in wound healing and regeneration. Notably, ΔNp63 stimulates EGFR signaling, which is used in wound healing to promote rapid multiplication of cells.

“Although this is not what we expected to see, it makes a lot of sense because the process of metastasis requires active proliferation,” Lambert says. “Metastatic cancer cells need both the properties of stem cells—such as the ability to self-renew and differentiate into different cell types—and the ability to multiply their numbers to grow new tumors.”

This finding may help to explain why qM cells are so uniquely good at metastasizing. Only in the qM state can the cells strongly stimulate EGFR signaling and so promote their own proliferation.

“This work gives us some mechanistic understanding of what it is about the quasi-mesenchymal state that drives metastatic tumor growth,” says Weinberg, who is also the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology.

The researchers hope that these insights could eventually contribute to therapies that prevent metastasis. They also hope to pursue further research into the role of ΔNp63. For example, this work illuminated a possible connection between ΔNp63 and the activation of dormant cancer cells, the cells that travel to new tissues but then cannot proliferate after they arrive there. Such dormant cells are viewed as ticking time bombs, as at any point they may reawaken. Lambert hopes that further research may reveal new insights into what causes dormant cancer cells to eventually gain the ability to grow tumors, adding to our understanding of the mechanisms of metastatic cancer.

Notes

Arthur W. Lambert, Christopher Fiore, Yogesh Chutake, Elisha R. Verhaar, Patrick C. Strasser, Mei Wei Chen, Daneyal Farouq, Sunny Das, Xin Li, Elinor Ng Eaton, Yun Zhang, Joana Liu Donaher, Ian Engstrom, Ferenc Reinhardt, Bingbing Yuan, Sumeet Gupta, Bruce Wollison, Matthew Eaton, Brian Bierie, John Carulli, Eric R. Olson, Matthew G. Guenther, Robert A. Weinberg. “ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.” Developmental Cell, Volume 57, Issue 24,
2022, 2714-2730.e8, https://doi.org/10.1016/j.devcel.2022.11.015.

Sally Kornbluth

Education

  • Graduate: PhD, 1989, Rockefeller University
  • Undergraduate: BA, 1982, Political Science, Williams College; BS, 1984, Genetics, Cambridge University

Research Summary

Sally Kornbluth is President of MIT. Before she closed her lab to focus on administration, her research focused on the biological signals that tell a cell to start dividing or to self-destruct — processes that are key to understanding cancer as well as various degenerative disorders. She has published extensively on cell proliferation and programmed cell death, studying both phenomena in a variety of organisms. Her research has helped to show how cancer cells evade this programmed death, or apoptosis, and how metabolism regulates the cell death process; her work has also clarified the role of apoptosis in regulating the duration of female fertility in vertebrates.

Honors and Awards

  • Member, American Academy of Arts and Sciences, 2020
  • Member, National Academy of Inventors, 2018
  • Member, National Academy of Medicine, 2013
  • Distinguished Faculty Award, Duke Medical Alumni Association, 2013
  • Basic Science Research Mentoring Award, Duke University School of Medicine, 2012

Previous Administrative Leadership Positions

  • Provost, Duke University, 2014 – 2022
  • Vice Dean for Basic Sciences, Duke University School of Medicine, 2006 – 2014
Honoring Salvador Luria, longtime MIT professor and founding director of the MIT Center for Cancer Research

Koch Institute event celebrates the new MIT Press biography “Salvador Luria: An Immigrant Biologist in Cold War America.”

Kate Silverman Wilson | MIT Press
November 18, 2022

On Oct. 26, the Koch Institute for Integrative Cancer Research at MIT and the MIT Press Bookstore and the co-hosted a special event launching the new biography “Salvador Luria: An Immigrant Biologist in Cold War America,” by Rena Selya. The book explores the life of longtime MIT professor Salvador Luria (1912–1991), whose passion for science was equaled by his commitment to political engagement in Cold War America.

Luria was born in Italy, where the Fascists came to power when he was 10. He left Italy for France due to the antisemitic Race Laws of 1938, and then fled as a Jewish refugee from Nazi Europe, making his way to the United States. Once an American citizen, Luria became a grassroots activist on behalf of civil rights, labor representation, nuclear disarmament, and American military disengagement from the Vietnam and Gulf wars. Luria joined the MIT faculty in 1960 and was later the founding director of the MIT Center for Cancer Research (CCR), which is now the Koch Institute. Throughout his life he remained as passionate about his engagement with political issues as about his science, and continued to fight for peace and freedom until his death.

As inaugural director of the CCR, Luria secured status and funding as a National Cancer Institute basic cancer center to embark on what were then the vast unknowns of cancer biology, oversaw the physical transformation of a former chocolate factory into a research facility, recruited brilliant young scientists to form its founding faculty, and helped foster a culture of scientific rigor, innovation, and excellence that ultimately helped set the standard for the field.

MIT Institute Professor Philip Sharp and Daniel K. Ludwig Professor for Cancer Research Richard Hynes, both founding faculty at the CCR, participated in the special event. Speaking of the center’s earliest days, Hynes explained, “There was an awful lot of cooperation, which was key in the success of this institution. I credit that to Salva and David [Baltimore] in particular. And it’s continued. Because when you grow up in that sort of environment you learn to repeat it.” The discussion was moderated by Deborah Douglas, director of collections and curator, science and technology at the MIT Museum.

Blacklisted from federal funding review panels but awarded a Nobel Prize for his research on bacteriophages, Luria was as much an activist as a scientist. In this first full-length biography of Luria, Selya draws on extensive archival research; interviews with Luria’s family, colleagues, and students; and FBI documents obtained through the Freedom of Information Act to create a compelling portrait of a man committed to both science and society.

The event was fittingly held in the Salvador E. Luria Auditorium at the Koch Institute. Quoting Zella Hurwitz Luria, Luria’s wife, Selya said, “‘Let us celebrate Salva’s life, his humanity, his struggle for understanding life and its biophysical basis, his sense of deep and personal fulfillment at having helped to build what he believed to be the best biology department in the country, his driving need to see justice done, his struggle for a peaceful, democratic world, his real interest in knowing people unlike himself and his love of his family, friends and, coworkers.’ More than 30 years later, it is an honor and pleasure for me to do just that here in the Salvador E. Luria Auditorium.”

Nanosensors target enzymes to monitor and study cancer

By analyzing enzyme activity at the organism, tissue, and cellular scales, new sensors could provide new tools to clinicians and cancer researchers.

Bendta Schroeder | Erika Reinfeld | Koch Institute
November 2, 2022

Cancer is characterized by a number of key biological processes known as the “hallmarks of cancer,” which remodel cells and their immediate environment so that tumors can form, grow, and thrive. Many of these changes are mediated by specific genes and proteins, working in tandem with other cellular processes, but the specifics vary from cancer type to cancer type, and even from patient to patient.

Sensitive tools for measuring protein or gene expression, even on the single cell level, have helped researchers understand the different cell types present in a tumor’s microenvironment and how this composition changes after treatments. However, these assays don’t necessarily show which proteins are active or relevant to tumor progression, or allow clinicians to noninvasively monitor the progress of the disease or its response to treatment. A protein could be present in a cancer cell as a bystander, for example, but not an active participant in its cellular transformations. Enzymes, which catalyze biochemical reactions inside cells, may give a clearer picture of which genes or proteins to target at a particular time.

In work recently published in Nature Communications, researchers from the MIT Koch Institute for Integrative Cancer Research have developed a set of enzyme-targeting nanoscale tools to monitor cancer progression and treatment response in real time, map enzyme activity to precise locations within a tumor, and isolate relevant cell populations for analysis.

“We hope that this new suite of tools can be useful in the clinic and the lab alike,” says Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology, professor of electrical engineering the computer science, and senior author of the study. “With further development, the nanosensors could be used by clinicians to tailor treatments to a patient’s specific cancer, and to monitor cancer progression and treatment response, while researchers could use them to better understand the molecular biology of cancer and develop new tools to diagnose, track, and treat the disease.”

Bhatia is also a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science. The study, conducted in collaboration with the laboratory of Tyler Jacks, was led by Ava Amini (Soleimany) ’16, a former graduate student from the Bhatia laboratory; and postdoc Jesse Kirkpatrick, also from the Bhatia lab.

Tracking tumors in real time

For several years, the Bhatia laboratory has been developing noninvasive urine tests for the detection of cancer, including colon, ovarian, and lung cancer. The tests rely on nanoparticles that interact with tumor proteins called proteases. Proteases are a type of enzyme that act as molecular scissors to cleave proteins and break them down into smaller components. Proteases help cancer cells escape from tumors by cutting through the extracellular network of proteins that holds cells in place.

The nanoparticles are coated with peptides (short protein fragments) that target cancer-linked proteases. When the nanoparticles arrive at the tumor site, the peptides are cut and release biomarkers that can be detected in the urine.

In the current study, the researchers tested whether they could use this technology not just to detect cancer, but to track the development of cancer and its response to treatments accurately and sensitively over time. The team created a panel of 14 nanoparticles designed to target proteases overexpressed in non-small cell lung cancer induced in a mouse model. These nanoparticles had been adapted to release barcoded peptides when they encounter dysregulated enzymes in the tumor microenvironment.

Each nanosensor was able to track different patterns of protease activity, which changed dramatically as the tumor progressed. After treatment with a lung cancer-targeting drug, the researchers were able to find signs tumor regression quickly, within just three days of administering treatment.

Cell maps and populations

While the existing nanosensor technique could be used to track tumor progression and treatment response in general, by itself, it could not shed any light on the specific cellular process at work.

“Like many of the tools available to assess molecular markers for cancer, our urine reporter treats the body like a black box,” says Kirkpatrick. “While we get some information about the state of the disease, we wanted to know more about the cells or proteins that are causing the disease to behave in a particular way.”

Having identified nanosensors of interest, researchers mapped where in the tumor microenvironment the enzymes acting on these sensors were active. They adapted their nanoprobes to leave behind fluorescent tags when they are cleaved from the nanosensor, assigning different tags to different proteases. After applying the nanoprobes to samples of lung tissue, they looked for patterns in how the tags were distributed.

One tag resulted in a curious spindle-like pattern that turned out to belong to the tumor vasculature. Researchers pinpointed the protease activity to specific types of cells: endothelial cells, which line blood vessels, and pericytes, which regulate vascular function and are actively recruited in angiogenesis — one of the archetypal hallmarks of cancer cell growth. Angiogenesis allows tumor cells to recruit existing blood vessels and stimulate new ones to form, in order to obtain the nutrients needed for tumor formation and progression.

Using their nanoprobes to label and sort cells based on their enzymatic activity, the team identified populations of cells associated with vasculature that displayed heightened expression of genes related to angiogenesis. The researchers also found evidence of signaling between pericytes and the endothelial cells that together comprise angiogenic blood vessels in vascular tissue.

Hallmark observations

In future work, the team seeks to identify the specific protease active in pericytes and dissect its role in angiogenesis. With this knowledge, they hope to develop formulations of therapies that can be delivered to patients to disrupt the recruitment and formation of blood vessels associated with tumor growth.

Ultimately, however, the team envisions panels of nanoprobes targeting several important features of cancer simultaneously and noninvasively in patients. Other hallmarks of cancer include proliferative signaling, the evasion of growth suppressors, genome instability, resistance to cell death, deregulated metabolism, and activation of invasion and metastasis. Because cancer alters protease activity across all of these processes, the team’s nanoprobes could be designed to target these different processes, with the aim of providing a comprehensive picture of tumor activity driving the disease. The approach could be used by researchers looking to investigate key biological phenomena in cancer models, as well as by clinicians seeking to monitor cancer progression noninvasively and select treatments for their patients.

The study was supported, in part, by the Virginia and D.K. Ludwig Fund for Cancer Research, the Koch Institute Frontier Research Program through a gift from Upstage Lung Cancer, the Koch Institute’s Marble Center for Cancer Nanomedicine, and Johnson & Johnson.

Introducing the Amon Award Winners
MIT Koch Institute
October 25, 2022

Cheers to the inaugural winners of the Koch Institute’s Angelika Amon Young Scientist Award, Alejandro Aguilera and Melanie de Almeida. The new award recognizes graduate students in the life sciences or biomedical research from institutions outside the U.S. who embody Dr. Amon’s infectious enthusiasm for discovery science.

Aguilera, a student at the Weizmann Institute of Science in Israel, has developed a platform for studying mammalian embryogenesis. De Almeida, who recently completed her doctoral work at the Research Institute of Molecular Pathology in Austria, develops CRISPR screens to explore cancer vulnerabilities and gene regulatory networks.

Aguilera and de Almeida will visit the Koch Institute in November to deliver scientific presentations to the MIT community and Amon Lab alumni.

Four from MIT receive NIH New Innovator Awards for 2022

Awards support high-risk, high-impact research from early-career investigators.

Phie Jacobs | School of Science
October 4, 2022

The National Institutes of Health (NIH) has awarded grants to four MIT faculty members as part of its High-Risk, High-Reward Research program.

The program supports unconventional approaches to challenges in biomedical, behavioral, and social sciences. Each year, NIH Director’s Awards are granted to program applicants who propose high-risk, high-impact research in areas relevant to the NIH’s mission. In doing so, the NIH encourages innovative proposals that, due to their inherent risk, might struggle in the traditional peer-review process.

This year, Lindsay Case, Siniša Hrvatin, Deblina Sarkar, and Caroline Uhler have been chosen to receive the New Innovator Award, which funds exceptionally creative research from early-career investigators. The award, which was established in 2007, supports researchers who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Lindsay Case, the Irwin and Helen Sizer Department of Biology Career Development Professor and an extramural member of the Koch Institute for Integrative Cancer Research, uses biochemistry and cell biology to study the spatial organization of signal transduction. Her work focuses on understanding how signaling molecules assemble into compartments with unique biochemical and biophysical properties to enable cells to sense and respond to information in their environment. Earlier this year, Case was one of two MIT assistant professors named as Searle Scholars.

Siniša Hrvatin, who joined the School of Science faculty this past winter, is an assistant professor in the Department of Biology and a core member at the Whitehead Institute for Biomedical Research. He studies how animals and cells enter, regulate, and survive states of dormancy such as torpor and hibernation, aiming to harness the potential of these states therapeutically.

Deblina Sarkar is an assistant professor and AT&T Career Development Chair Professor at the MIT Media Lab​. Her research combines the interdisciplinary fields of nanoelectronics, applied physics, and biology to invent disruptive technologies for energy-efficient nanoelectronics and merge such next-generation technologies with living matter to create a new paradigm for life-machine symbiosis. Her high-risk, high-reward proposal received the rare perfect impact score of 10, which is the highest score awarded by NIH.

Caroline Uhler is a professor in the Department of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society. In addition, she is a core institute member at the Broad Institute of MIT and Harvard, where she co-directs the Eric and Wendy Schmidt Center. By combining machine learning, statistics, and genomics, she develops representation learning and causal inference methods to elucidate gene regulation in health and disease.

The High-Risk, High-Reward Research program is supported by the NIH Common Fund, which oversees programs that pursue major opportunities and gaps in biomedical research that require collaboration across NIH Institutes and Centers. In addition to the New Innovator Award, the NIH also issues three other awards each year: the Pioneer Award, which supports bold and innovative research projects with unusually broad scientific impact; the Transformative Research Award, which supports risky and untested projects with transformative potential; and the Early Independence Award, which allows especially impressive junior scientists to skip the traditional postdoctoral training program to launch independent research careers.

This year, the High-Risk, High-Reward Research program is awarding 103 awards, including eight Pioneer Awards, 72 New Innovator Awards, nine Transformative Research Awards, and 14 Early Independence Awards. These 103 awards total approximately $285 million in support from the institutes, centers, and offices across NIH over five years. “The science advanced by these researchers is poised to blaze new paths of discovery in human health,” says Lawrence A. Tabak DDS, PhD, who is performing the duties of the director of NIH. “This unique cohort of scientists will transform what is known in the biological and behavioral world. We are privileged to support this innovative science.”

MIT biologist Richard Hynes wins Lasker Award

Hynes and two other scientists will share the prize for their discoveries of proteins critical for cellular adhesion.

Anne Trafton | MIT News Office
September 28, 2022

MIT Professor Richard Hynes, a pioneer in studying cellular adhesion, has been named a recipient of the 2022 Albert Lasker Basic Medical Research Award.

Hynes, the Daniel K. Ludwig Professor for Cancer Research and a member of MIT’s Koch Institute for Integrative Cancer Research, was honored for the discovery of integrins, proteins that are key to cell-cell and cell-matrix interactions in the body. He will share the prize with Erkki Ruoslahti of Sanford Burnham Prebys and Timothy Springer of Harvard University.

“I’m delighted, and it’s a pleasure to be sharing it with them,” Hynes says. “It’s great for the field, and for the trainees who did much of the work.”

Hynes’ research focuses on proteins that allow cells to adhere to each other and to the extracellular matrix — a mesh-like network that provides structural support for cells. These proteins include integrins, a type of cell surface receptor, and fibronectins, a family of extracellular adhesive proteins. Integrins are the major adhesion receptors connecting the extracellular matrix to the intracellular cytoskeleton.

During embryonic development, cell adhesion is critical for cells to move to the correct locations in the embryo. Hynes’ work has also revealed that dysregulation of cell-to-matrix contact plays an important role in cancer cells’ ability to detach from a tumor and spread to other parts of the body, in a process known as metastasis.

“Professor Hynes’ contributions to the field of cancer biology, and more broadly, cellular biology, are numerous,” says Nergis Mavalvala, the Curtis and Kathleen Marble Professor of Astrophysics and the dean of the School of Science. “His investigations of fundamental biological questions — How do cells interact? How do they stick together? — changed how scientists approach cancer research and opened up avenues in developing potential therapeutics to disrupt metastatic disease.”

Born in Kenya, Hynes grew up in Liverpool, in the United Kingdom. Both of his parents were scientists: His father was a freshwater ecologist, and his mother a physics teacher. Hynes and all three of his siblings followed their parents into scientific fields.

“We talked science at home, and if we asked questions, we got questions back, not answers. So that conditioned me into being a scientist, for sure,” Hynes says.

After earning his bachelor’s and master’s degrees in biochemistry at Cambridge University, Hynes decided to head to the United States to continue graduate school. Colleagues at Cambridge suggested MIT, so he came to the Institute and earned his PhD in 1971. After doing a postdoc at the Imperial Cancer Research Fund Laboratories in London, he returned to MIT in 1975 as a faculty member in the Department of Biology and a founding member of MIT’s Center for Cancer Research (the predecessor of today’s Koch Institute).

Hynes began his career as a developmental biologist, studying how cells move to the correct locations during embryonic development. As a postdoc, he began studying the differences in the surface landscapes of healthy cells and tumor cells. This led to the discovery of a protein called fibronectin, which is often lost when cells become cancerous.

He and others found that fibronectin is part of the extracellular matrix, the network of proteins and other molecules that support cells and tissues in the body. When fibronectin is lost, cancer cells can more easily free themselves from their original location and metastasize to other sites in the body. Cells bind to the matrix through cell surface receptors known as integrins. In humans, 24 integrin proteins have been identified. These proteins help give tissues their structure, enable blood to clot, and are essential for embryonic development.

“These cell-matrix adhesion proteins hold us all together,” Hynes says. “If we didn’t have them, we’d be a pool of cells on the floor. And they’re contributors to lots of diseases: fibrosis, cancer, thrombosis, immune and autoimmune diseases. So, cell adhesion has become a huge field at both the basic science level and the therapeutic level.”

Since joining the MIT faculty, Hynes has also served as head and associate head of the Department of Biology, and as director of the Center for Cancer Research. He has also served as scientific governor of the Wellcome Trust in the United Kingdom, and as co-chair of National Academy committees establishing guidelines for stem cell and genome editing research.

His many awards include the Gairdner Foundation International Award, the Distinguished Investigator Award from the International Society for Matrix Biology, the Robert and Claire Pasarow Medical Research Award, the E.B. Wilson Medal from the American Society for Cell Biology and the Paget-Ewing Award, Metastasis Research Society. Hynes is also a member of the National Academy of Sciences, the National Academy of Medicine, the Royal Society of London, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences.

The Lasker Award comes with a $250,000 prize, which will be shared between the three recipients.