727 E. Tyler St. Tempe
Clonal Analyses and Clinical Behaviors of Human Cancer
Cancer, in general, is thought to evolve from natural selection of cells within a neoplasm. While this hypothesis is still being refined, it is widely accepted that competition amongst neoplastic clones, coupled with genetic changes and environment, are integral to cancer. Genomic instability appears to cooperate with Darwinian selection to promote cancer formation through a process in which genomic aberrations occur at accelerated rates, and those alterations that provide a selective growth advantage lead to clonal evolution and expansion. The fundamental hypothesis of our studies is that cancers consist of heterogeneous populations that can rapidly respond to stress (e.g. cytotoxic therapies) by exploiting fundamental principles of evolution. These behaviors are of major clinical significance for both primary and metastatic cancers where distinct clonal populations of tumor cells with variable evolutionary fitness are dispersed to multiple sites within a patient. Our long-range objective is to develop new therapeutic options for patients with cancer including advanced metastatic pancreatic ductal adenocarcinoma (PDA).Towards this goal we are using flow cytometric sorting strategies to identify and purify diploid and aneuploid cell populations in each sample of interest. These then are comprehensively profiled with high resolution genomic tools to define clinical contexts in each patient. Genes associated with pathways disrupted by selected clonal aberrations in neoplastic genomes in vivo can then be functionally interrogated in RNAi-based assays to evaluate their potential as therapeutic targets. Validated “hits” that target genes essential for the evolution, maintenance, or persistence of neoplastic cell lineages represent highly favorable candidates for improved therapeutic strategies. I will discuss some of our recent findings in PDA genomes and the role of clonal behaviors in mediating therapeutic responses.