AbstractAt their most fundamental level, cancers are initiated by genetic alterations that drive hyperactive cell divisionand cell migration. A common therapeutic strategy has been to target the proteins in the often-mutatedsignaling pathways that regulate cell proliferation. However, so far this strategy has achieved only limitedsuccess despite large public and private investment, which is likely due to functional redundancies in signalingpathways that give multiple avenues for the emergence of drug-resistance. An alternative strategy, whichdefines the organizing framework of our Center, is to directly target the internal or external mechanicalmachinery or structural elements that drive cell migration. As it is these elements that serve as the mostdownstream convergence point of the upstream genetic alterations, disruption of these critical elementsprovides viable, clinically-relevant targets. Since cell migration is a common feature of high-grade cancer, andinvasion and metastasis are the primary cause of cancer related death, our Center will focus on understandingthe fundamental mechanics and chemistry of how cells generate forces to move through complex andmechanically challenging tumor microenvironments. By focusing directly on the ?nuts and bolts? of cellmigration, we will be targeting the most vital and non-redundant part of the system. Specifically, we proposeintegrated modeling and experiments to investigate the molecular mechanics of cell migration and how thetumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. Wewill experimentally test our computational cell migration simulator, v1.0 (CMS1.0) for the mechanical dynamicsof cell migration that will ultimately be used to: 1) identify novel drug targets/target combinations in silico, 2)define molecular mechanical subtypes of tumors for patient stratification, 3) guide the engineering of in vitromicrosystems and in vivo animal models to better mimic the human disease, and 4) simulate tumorprogression under different potential treatment strategies. Finally, we will develop a simulator-driven reversegenetics approach to elucidate the functional mechanical consequences of driver mutations and seek tomanipulate the physical characteristics of a tumor to simultaneously bias against immune suppressor cells andpromote the antitumor immune response.
|Effective start/end date||8/17/16 → 7/31/21|
- National Institutes of Health: $190,106.00
- National Institutes of Health: $1,666,953.00