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Cancer Cell Biology Program: Matchmaker to Interdisciplinary Researchers

These intravital microscopy images show blood vessels (red) and tumor cells (green nuclei) expressing the chromatin marker H2b-EGFP before (left) and after 4 days of Taxol treatment (right). The presence of small, clustered mutlinuclei on the right is a biomarker for cellular response to Taxol. The images were taken by James Orth (Mitchison lab) and Rainer Kohler (Weissleder lab) using fluorescent, confocal microscopy of an engineered tumor model that allows for repeated, non-invasive imaging of the tumor cells during drug response.

Conquering cancer is too daunting for any one discipline, approach, or individual. It requires melding the insights from multiple disciplines – cancer biology, chemistry, systems biology, genomics, signal processing, image analysis, to name a few. Some of these insights come from working bench to bedside, following a molecular discovery through to clinical application. Other insights lead from the bedside to the bench, taking a clinical observation about cancer and ferreting out its molecular basis in the cancer cell. Almost never does one lone research laboratory span enough disciplines or use enough approaches to see how its own discoveries, groundbreaking though they may be, fit into the larger, complex scheme of cancer. To make headway against cancer, researchers need the diverse contributions of many others, often in unrelated fields. Under the direction of Program Leaders Andrea McClatchey, PhD (MGH), and David Pellman, MD (DFCI), the goal of the DF/HCC Cancer Cell Biology Program is to foster such interdisciplinary interactions and bring together researchers from different fields who are, perhaps unbeknownst to them, working on different angles of the same problem.

“This is the only way biomedical research can work,” says cell biologist and biochemist John Blenis, PhD (HMS). Along with systems biologist Lewis Cantley, PhD (BIDMC), Blenis took the unexplained phenomenon that cell metabolism is altered in cancer and with the contributions of many other labs elucidated the differing molecular mechanisms for funneling energy through normal cells and cancer cells, uncovered new targets for cancer therapy, and developed new, possibly clinically relevant ways to measure cellular metabolism. “Very few labs can make basic research discoveries, identify potential targets for drug or bioassay development, become engaged in drug development, begin preclinical studies, and bring the drug to the clinic. We need collaborations with investigators engaged in different aspects of research with the common goal to cure cancer. The Program provides the scientific community with the environment to make this happen.”

Making Matches

But how do these interdisciplinary collaborations come together when researchers from different departments involved in specialized fields might never realize that they are working on related problems? “We are matchmakers to the interdisciplinary cancer community within DF/HCC,” say McClatchey and Pellman, who were appointed as Program Leaders in April 2010 and have been recruiting more experts in systems biology, translational studies, stem cell biology, and technology development.

“We have always had a remarkable pool of outstanding basic scientists who are gaining insights into how cancer cells work and developing novel technologies,” says Pellman, a pediatric oncologist and cell biologist who studies the mechanism of cell division. “But we needed a venue to connect with physicians who could translate this exciting research into the clinic. We want people to meet and say, ‘Aha! You have a new result on cancer metabolism. We can assay that in patients in a unique way.’”

McClatchey, a basic cancer cell biologist, relates how spontaneous matchmaking invigorated her research on an inherited tumor syndrome called neurofibromatosis 2 (NF2). She was investigating how cells organize receptors across membranes and discovered that the major protein she studies, Merlin, controls the receptor EGFR. Previously, biological chemist Nathanael Gray, PhD (DFCI) had identified a cancer-driving EGFR mutation in some lung cancer cells that ultimately led to the development of Tarceva and Iressa, drugs that inhibit those mutant cancer cells – initiating a radical shift towards treating solid tumors with targeted therapies. “I was interested in the translational impact of our work on EGFR,” McClatchy continues, “so I began communicating with people at MGH and DFCI who were studying it in lung cancer and doing translational work on receptors,” including Jeff Engelman, MD, PhD (MGH). Such connections can be mutually beneficial. “Thinking about EGFR through their translational ‘lens’ can benefit my work, while our discoveries of basic mechanisms of EGFR regulation can inform their strategies for therapeutically targeting EGFR.”

Following the Energy

Cancer cell biology seeks to understand the basic mechanisms of how cells normally work and then exploit that knowledge to understand how processes go awry in tumor cells. A major challenge involves delineating how signaling systems differ between normal and cancer cells and identifying new nodes in those pathways to target with novel therapeutics. A long-term collaboration among Program members and others helped define the major signaling systems (Ras/MAP kinase, PI3 kinase, mTOR, S6 kinase) that are dysregulated in most cancer cells – and that are targeted by every major pharmaceutical company in the world. Blenis, for example, showed that PI3K, mTOR, and S6K functioned in a major cancer pathway,and that revealed new drug-able nodes.

A breakthrough came when an investigation of cancer cells that increased metabolism suggested an entirely new mechanism for targeting cancer cells. Starting in 2005, Blenis and colleagues discovered that mTOR and S6K play a major role in protein synthesis, which is needed for cell growth and proliferation and is among the most energy intensive cellular processes. In cancer, mTOR is always on, promoting constant protein synthesis. Blenis wondered, “How does the cell meet the huge new energy demand of this cellular race car? Does it utilize new types of ‘high-octane’ fuel? Does it adapt its engine so it can use the new fuel sources?”

Cancer cells use lots of glucose, but Blenis’s lab identified the amino acid glutamine as another important specialized fuel. “Cells with hyperactivated mTOR have a very difficult time surviving without glutamine. If we take away both glutamine and glucose, tumor cells die but normal cells can live by shutting down growth and energy use.”

After finding that inhibiting glutamine metabolism had the same effect on cancer cell growth and survival as taking away glutamine itself, Blenis’s group searched for compounds that inhibit enzymes involved in glutamine metabolism. They reported in 2010 that epigallocatechin gallate or EGCG (extracted from green tea) inhibited glutamate dehydrogenase – and killed energetically-stressed tumor cells with mTOR hyperactivation, but not normal cells. EGCG is too unstable in the human body to be a drug, but it could inspire a new class of anti-cancer drugs that selectively kill mTOR-addicted cancers.

Translating this discovery into clinical research will require a sensitive bioassay for identifying which patients have tumors that are glutamine addicted and thus potentially sensitive to glutamine metabolism inhibitors. Blenis is identifying small molecules in high-throughput screens to begin this path to the clinic. “As we make progress, we hope to identify others in the cancer community interested in translating our findings.” [See related sidebar.]

Functionalizing the Cancer Genome

Many headlines about cancer highlight the discovery of new cancer genes. Cancer cell biology benefits from cancer genetics, but it also requires the broader view of biochemistry, systems biology, signaling pathways, and more. “Defining genetic abnormalities is important,” says Pellman, “but it doesn’t tell us about the functional consequences. We want to functionalize genomic changes, and that’s done on many levels through our program.” Some Program researchers study how a specific mutation works in the cell. Others explore how mutated proteins are structurally altered and how that makes them behave differently in the cell. Some investigate how small molecules interact specifically with altered proteins, and others are designing novel therapies based on that knowledge.

A key goal of the Program is to harness these discoveries, disseminate them, and apply them to the clinic. “We need to get more cell biology experts interested in working on cancer,” says McClatchey, “and also get existing cancer cell biologists interested in clinical and translational work.” Timothy Mitchison, PhD (HMS), a noted cell biologist who now “obsesses” about the cancer drug pacitaxel, or Taxol, exemplifies the type of individual the Program is interested in cultivating.

Obsessing about Taxol

For Mitchison, the conversion from a basic cell biologist interested in cell division to one interested in cancer, cancer therapies, and translational work started when pharmaceutical companies wanted to develop a 1999 discovery in his lab into a new class of drugs. The compound, Monastrol, had a unique way of blocking mitosis by inhibiting kinesin-5 motor proteins that help form bipolar spindles in dividing cells. Researchers expected it would have the same anti-cancer activity as the anti-mitotic drug pacitaxel, or Taxol, which is widely used for breast cancer and other solid tumors. However, Monastrol dashed those hopes.

“I was upset that a drug we’d help develop was failing while a comparative anti-mitotic medication worked,” Mitchison says. To discover why, he started working on cancer cell lines in his own lab – from a therapeutic perspective. “In five years, I went from knowing nothing about cancer to becoming interested in cancer treatment.”

He wanted to see the cellular processes in real tumors in the body, not just in cell cultures. So in 2009, he teamed up with Ralph Weissleder, MD, PhD (MGH), a radiologist and systems biologist with tools for intravital imaging in mouse models. With that technology, Mitchison could see individual cells in a tumor and look inside them.

“We quickly learned that the textbook understanding of Taxol was wrong,” says Mitchison. “It was based on studying cancer in a petri dish, but Taxol acts very differently in mice. So Taxol must have some additional activity in tumors not related to mitosis. What is that something else?”

Mitchison and his collaborators in systems biology think Taxol’s additional activity in the body may involve stopping cancer cell growth. They have a marker that measures cellular response to the drug in mice. But is it relevant in humans, and can it predict which patients will respond to the drug? They hope to test this measure in patients undergoing neoadjuvant breast cancer therapy to shrink tumors before surgical removal, biopsying the tumor soon after Taxol treatment begins.

Mitchison wants to study other chemotherapies, why they sometimes fail, and how to improve them. Targeted therapies may be the future, but meanwhile physicians still rely on conventional drugs for most patients – drugs that act on the cell division mechanisms he studies. “It’s a little retro,” he acknowledges, “but we’re doing it in a modern way.”

Imaging Cancer Cells

Gaudenz Danuser, PhD (HMS), a computational biologist and expert in quantitative image analysis and mathematical models has also developed powerful technologies for a systems approach for studying cancer cells. For example, he combines automated tracking, data analysis, and visualization tools for imaging fluorescently-labeled proteins and signaling pathways. Researchers can see at high resolution how cancer cells and normal cells differ and how proteins are networked within cells.

“It’s a great example of how the Cancer Cell Biology Program brings new ways of studying cancer to the community using a multi-disciplinary translational approach,” says Pellman. Eventually, this technology may be extended to imaging tumors in animal models and then people.

The next Cancer Cell Biology Program symposium, “Imaging the Cancer Cell” on March 29, 2012, will feature the work of Mitchison, Weissleder, Danuser, and others.

Mapping Proteins

In an age of large-scale genomic and functional screens, researchers have an overload of data with few methods to integrate the findings, identify the most important gene alterations, or understand how these alterations perturb normal cells. To facilitate that integration, the Program supports efforts to map protein-protein interactions. For example, ComPASS, a proteomics platform of Wade Harper, PhD (HMS), sifts through mass spectrometry data to identify all the proteins that associate with a specific protein.

McClatchey says this proteomic platform and better data analysis will facilitate more matchmaking. Basic cancer cell biologists discover how cell misbehavior contributes to tumor formation and metastasis. Now they can collaborate with proteomics experts to understand why these cells are misbehaving on a genetic and protein level. Conversely, genomics or proteomics experts may uncover a defective gene or protein in a cancer, but they need cancer cell biologists and systems biologists to understand how those defects affect the behavior of cells in a particular context.

All in all, there is a virtual explosion of researchers branching away from their individual research on cancer cell biology and collaborating so they can inform and motivate each other’s work. And that is why matchmaking looms so large in the Cancer Cell Biology Program.