Pathways are ordered series of actions that occur as cells move from one state, through a series of intermediate states, to a final action. Because model organisms – fruit flies, roundworms, yeast, zebrafish and others – are related to humans, they share many of the same pathways, but in systems that are much easier to study. Focusing on pathways in model organisms can therefore reveal new drug targets that may be useful in treating human disease.
"By reading evolution's notes, we can discover what really matters in the genome," keynote speaker Eric Lander, Ph.D., founding director of the Broad Institute of Harvard and MIT and professor of biology at MIT, told a packed crowd at the MOHB: Cancer Genetics Meeting on June 19.
What matters the most in the genome of a cancer cell may be the seeds of drug resistance, the genetic changes that enable cells to evade our best drugs. Bert Vogelstein, M.D., director of the Ludwig Center at Johns Hopkins University and an investigator with the Howard Hughes Medical Institute and a keynote speaker on June 17, told participants. He called drug resistance to single agents a "fait accompli," or a done deal as a side effect of the evolution of cancer.
"About 3,000 resistant cells are present in every visible metastasis," said Dr. Vogelstein. "That's why we see resistance with all therapeutics, even when they work. And we can't get around it with single agents. Cancer treatment requires combinations of agents."
Presentations throughout the meeting offered specific examples of events in pathways involved in the progression of cancer in model organisms that shed light on how human cancer may metastasize.
To identify the genes behind a breast cancer's spread to the lungs, Joan Massagué, Ph.D., chair of the Cancer Biology & Genetics Program at Memorial Sloan-Kettering Cancer Center and colleagues, placed cells from the lung fluid of patients into mice, deducing a "breast cancer lung metastasis signature" and identifying several mediators of metastasis that are clinically relevant and potential drug targets.
Denise Montell, Ph.D., from Johns Hopkins University School of Medicine, traced the signaling pathways that developing egg cells in the Drosophila (fruit fly) ovary use to migrate as using some of the same genes that are expressed as ovarian cancer spreads.
David Botstein, Ph.D., and his group at Princeton University use yeast to model the evolution of cancer through serial mutations, revealing that only a few destinations for a particular type of cancer are possible. "Breast cancers can't turn into leukemias, There are limited subtypes, not just anything can happen," he explained.
David Q. Matus, Ph.D., a postdoctoral researcher at Duke University, discussed an in vivo model of cell invasion, a key component of cancer metastasis that occurs during the larval development of the roundworm, Caenorhabditis elegans. He showed that the invasive gonadal anchor cell needs to exit the cell cycle, (be non-dividing), in order to invade. Proliferative anchor cells fail to form "invadopodia" -- invasive feet or protrusions in the basement membrane -- suggesting that cell division and cell invasion are disparate states.
The tumor suppressor "drivers" – those genes that reduce the probability of a cell turning into a cancer cell -- are often deletions -- part of a chromosome or a sequence of DNA that is missing. But, a drug can't target proteins encoded by such sequences. The solution? Understand and interrogate pathways. "For every mutated tumor suppressor gene that inactivates a component of a pathway, another gene is indirectly activated," Dr. Vogelstein explained. We need model organisms to dissect the pathways that will underlie future combination therapies, he concluded.
ABOUT THE MODEL ORGANISM TO HUMAN BIOLOGY MEETING: The GSA MOHB Meeting has been held every other year since 2006. The GSA Board of Directors developed this meeting to enable basic research scientists studying genetic diseases in model organisms and scientists studying these diseases in humans to have a forum for discussion of their findings and to forge collaborative investigations.
ABOUT GSA: Founded in 1931, the Genetics Society of America (GSA) is the professional membership organization for scientific researchers, educators, bioengineers, bioinformaticians and others interested in the field of genetics. Its nearly 5,000 members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level. GSA is dedicated to promoting research in genetics and to facilitating communication among geneticists worldwide through its conferences, including the biennial conference on Model Organisms to Human Biology, an interdisciplinary meeting on current and cutting edge topics in genetics research, as well as annual and biennial meetings that focus on the genetics of particular organisms, including C. elegans, Drosophila, fungi, mice, yeast, and zebrafish. GSA publishes GENETICS, a leading journal in the field and an online, open-access journal, G3: Genes|Genomes|Genetics. For more information about GSA, please visit www.genetics-gsa.org. Also follow GSA on Facebook at facebook.com/GeneticsGSA and on Twitter @GeneticsGSA.
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