Major grant funds research effort that seeks to understand complexity of invasive cancer

A $9.5 million, five-year grant from the National Cancer Institute (NCI) will fund an intensive multidisciplinary research effort that seeks to better understand how cancer cells reach an aggressive state and begin to damage surrounding tissue. The initiative, called Cancer Systems Biology at Yale ([email protected]), is one of four new research centers in NCI’s Cancer Systems Biology Consortium, and is directed by Andre Levchenko, Ph.D., the John C. Malone Professor of Biomedical Engineering and director of the Yale Systems Biology Institute.

[email protected] is based at the university’s West Campus and brings together investigators with varying research backgrounds from three schools and seven departments at the university, and a variety of other institutes and programs. In particular, at the core of [email protected], the Yale Systems Biology Institute on West Campus will join forces with the Yale Cancer Biology Institute, the Raymond and Beverley Sackler Institute for Biological, Physical and Engineering Sciences, the Yale Cancer Center, and Emory University to address fundamental questions at the core of cancer biology. Four of the 12 principal and primary investigators are members of the School of Medicine faculty.

The program will address the specific problem of phenotypic plasticity of invasive cancers. Cancer cells with the same genomic makeup can adopt different phenotypes, or characteristics, switching from rapid division and growth to invasive migration and metastatic spread through unknown mechanisms. Furthermore, different phenotypes may co-exist in the same tumor, with cells exchanging signals among themselves and with surrounding normal tissues. [email protected] will explore this complexity of invasive cancer through a range of novel techniques and approaches.

[email protected] will also be devoted to understanding and manipulating the complex molecular networks governing complex cell behaviors. A key focus of the research will be on translational applications aimed at identifying new targets for therapeutic intervention and the development of new drugs targeting invading cells.

Says Levchenko, “Our approach will vary from the use of synthetic biology to evolutionary approaches, and will rely heavily on advances in engineering, mathematics, and physics, in addition to breaking new ground in biology and chemistry.”

“The next important goal in cancer therapeutics will be to control or correct signaling networks rather than targeting individual molecules, and [email protected] brings unique sets of expertise and perspective together to do this,” says Mark A. Lemmon, Ph.D., co-director of the Yale Cancer Biology Institute and the David A. Sackler Professor of Pharmacology at the medical school.

Other School of Medicine investigators who plan to take full advantage of [email protected]’s advanced resources and collaborative approach include Jesse Rinehart, Ph.D., associate professor of cellular and molecular physiology. Rinehart says a portion of the grant will support a project that he and Farren J. Isaacs, Ph.D., an assistant professor of molecular, cellular, and developmental biology in the Yale Combined Program in the Biological and Biomedical Sciences, have developed.

“We’ve combined our expertise in an area called synthetic biology and molecular biology, to build very, very unique bacterial cells,” says Rinehart. “They’re unique because they allow us to encode human genes and then endow those human genes with the same physiological function that you might find in human cells. We recently demonstrated that we could bring in genes that are responsible for small protein networks or genetic networks in cancer, and that we could accurately model their properties in these bacterial cells.”

Rinehart, whose primary expertise is in signaling networks, says that as the work proceeds, the presence of additional disciplines such as mathematical modeling will be invaluable. “Mathematical models can combine real terms and real quantities with unknown variables, giving us a model that has flexibility and outcomes that are both predictable and testable.” Says Rinehart of [email protected] colleagues who have expertise beyond the biological sciences, “I really want to learn from them.”

Gunter P. Wagner, Ph.D., Alison Richard Professor of Ecology and Evolutionary Biology, is looking for ways to use the knowledge of normal physiological aggressive cell growth to understand and thwart the often-fatal metastasis of cancers in humans. He hopes to find clues in certain mammals for which the skin cancer melanoma has become a chronic, non-malignant condition. “Given all the molecular biology tools we have at our disposal it would not be surprising if we could find the gene regulatory differences that make the difference between cows and pigs on the one hand, and humans,” Wagner says.

Wagner will draw from Levchenko’s expertise in examining aggressive cancers in the context of surrounding biological matrix and normal stromal (connective tissue) cells. Levchenko views metastatic disease in military terms. “If you think about an invading army, it can be welcomed by the population or resisted. A lot depends on the country that is being invaded and the population that lives there. Very similarly in cancer you can think about what happens with the cells that are normal and experience the invasion of cancer cells. Are they going to resist? Or are they going to promote the invasive spread?”

Sidi Chen, Ph.D., assistant professor of genetics and systems biology, will use his lab’s expertise in designing experimental models to benefit CaSB and the field. “My role in this grant is to build a platform to study cancer in animal models,” says Chen. “We have previously developed the CRISPR/Cas gene editing technology in vivo in Cas9 transgenic mice. We want to utilize this platform to build new mouse models to better study cancer.”

A hallmark of [email protected] will be the opportunity for speed, efficiency, and new ways of attacking problems that collaboration brings. The moment any lab makes tangible progress, other investigators will know it. “We typically get to interact with ideas and progress from other labs after it’s been published,” says Rinehart. “Even when it’s a breakthrough, it’s something that the lab was working on in the past. Sometimes that may be five years ago. You really need to know what they are doing now, and that’s exactly what we have.”

Levchenko compares this approach to a famous precedent—the Manhattan Project—which brought together scientists from many disciplines with the urgent goal of developing an atomic bomb that could win World War II. “I don’t think a lot of people thought it was possible to do what is already happening here, including identification of new lead compounds that have the potential to become anti-cancer drugs, in just a few years of our active work. We are dealing with one of the most difficult problems in medicine and the hope was that with harnessing all the interdisciplinary approaches, this problem can be solved—and the progress has been very impressive.”

Lemmon believes the benefits of collaboration, with an emphasis on systems biology over studying components of cancer in isolation, may bring progress that is “beyond exponential.” Argues Lemmon, “The emergent properties won’t emerge—you’ll never know what they are—unless you take a systems approach. So, if you’re actually trying to understand the properties of the system, you will never understand it by looking at the parts.”

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