Project 4: Modeling neoplastic progression and analyzing genomic data to characterize the load of driver and passenger mutations in cancer. The development ofcancer can be considered as an evolutionary process within an organism. During neoplastic progression, cells acquire mutations, compete for resources, and are subject of selection for ability to grow fast in a complex and dynamic environment. These processes of Darwinian evolution have been systematically studied and modeled mathematically by methods similar to those used in Statistical Mechanics and related fields of Physics. As a result of somatic micro-evolution a population of cancer cells harbors multiple mutations: a few driver mutations essential for neoplastic progression, and many more passenger mutations. Classical works in population genetics have demonstrated that accumulation of mutations lead to increased genetic load, i.e. reduction in the mean fitness, and can lead to population extinction. Our hypothesis is that increasing the genetic load of mutations present in the population of cancer cells can make the population shrink to extinction, a process that we call clonal extinction. This idea can pave a way to a potentially novel approach to cancer treatment by therapeutics that unleash the deleterious effects of harbored mutations. To the best of our knowledge the idea of exploiting accumulated mutations to push a population of cancer cells into extinction has not been put forward. We propose to test this hypothesis by a unique approach that combines development of a theory of neoplastic evolution, analysis of emerging massive cancer genomics data, and experimental study of passenger mutation and their impact of cancer development. The experiment will reproduce seminal Luria-Delbruck experiment applied to cancer cell. Our data-driven theoretical approach is rooted in fifty years of evolutionary genetic thought about the genetic load and its consequences for population extinction.

Public Health Relevance

Developed theory of cancer micro-evolution can help to elucidate several phenomena in cancer development. If successful, our study of passenger mutations can offer a potentially novel approach to cancer treatment. This approach use cancers'own internal weakness - numerous accumulated mutations - to bring the population of cancer cells down. Characterization of cancer mutations can provide avenues for dfivfilonment of new anti-cancer driins and heln eluddatina the of action of exciting ones

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
United States
Zip Code
Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda et al. (2014) Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep 6:514-27
Semrau, Stefan; Crosetto, Nicola; Bienko, Magda et al. (2014) FuseFISH: robust detection of transcribed gene fusions in single cells. Cell Rep 6:18-23
Knouse, Kristin A; Wu, Jie; Whittaker, Charles A et al. (2014) Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A 111:13409-14
Mizuguchi, Takeshi; Fudenberg, Geoffrey; Mehta, Sameet et al. (2014) Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe. Nature 516:432-5
Barreca, A; Martinengo, C; Annaratone, L et al. (2014) Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma. Blood Cancer J 4:e249
McFarland, Christopher D; Mirny, Leonid A; Korolev, Kirill S (2014) Tug-of-war between driver and passenger mutations in cancer and other adaptive processes. Proc Natl Acad Sci U S A 111:15138-43
Mentink, Remco A; Middelkoop, Teije C; Rella, Lorenzo et al. (2014) Cell intrinsic modulation of Wnt signaling controls neuroblast migration in C. elegans. Dev Cell 31:188-201
Polak, Paz; Lawrence, Michael S; Haugen, Eric et al. (2014) Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair. Nat Biotechnol 32:71-5
Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang et al. (2014) Genetic and phenotypic diversity in breast tumor metastases. Cancer Res 74:1338-48
Slavov, Nikolai; Budnik, Bogdan A; Schwab, David et al. (2014) Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis. Cell Rep 7:705-14

Showing the most recent 10 out of 48 publications