Understanding cancer heterogeneity

Cancer is a heterogeneous disease, with differences not only among different patients, but even amongst the bulk of cells within tumors in individual patients. Intra-tumoral heterogeneity is driven by multiple mechanisms, including dynamic genetic and epigenetic changes acquired by cancer cells during disease progression. These changes allow tumors to evolve and adapt as they grow, spread and undergo treatment. Elucidating causes and consequences of cancer heterogeneity is a high priority, as cancer heterogeneity likely impacts disease outcomes in patients such as the propensities to relapse and metastasize, development of therapy resistance and responsiveness to immunotherapy. This project will examine the origins of intra-patient heterogeneity in cancer, particularly melanoma, and link these to features of disease biology and therapy response, using exceptional resources and world-leading technologies for modeling and molecular profiling of human melanoma (Nature 456:593, Cancer Cell 18:510, Sci Transl Med 4:159ra149, Cancer Res 76:3965). The work will provide fundamental insights into cancer heterogeneity with a view to identifying and exploiting its drivers and effects on tumor biology. Aims. Project aims will depend on the degree sought, but potentially include: 1) Integrated 'omics' analysis of evolutionary and adaptive within-patient changes during cancer progression. 2) In vitro and in vivo modeling of cancer heterogeneity. 3) Functional interrogation of molecular drivers of cancer heterogeneity, evolution and adaptation. Methods/Techniques. The project will avail patient tissues, mouse models, flow cytometry, cell and molecular biology techniques, immunomolecular profiling and informatics approaches to evaluate and functionally dissect cancer heterogeneity Key references. Nature 545:175, Nature 456:593, Nature 439:993, Nature 439:84, Nat Cell Biol 9:201, J Natl Cancer Inst 98:1011, Nat Med 18:1239, Nat Biotech 4:1010, Cancer Research 68:7711, Cancer Research 76:3965