Thursday Seminar: Greg Sepich-Poore

Title: “Reconsidering clonal evolution as a multispecies process” Abstract: Cancer cells evolve through space and time, and the success of this evolution dictates survival or mortality of the human host. Although clonal evolution has traditionally centered on genetic alterations, non-genetic alterations (e.g., epimutations) frequently contribute, suggesting that broader definitions are necessary beyond mere cancer genomics. Given that recent research has comprehensively demonstrated the effects of extracellular and intracellular microbes on cancer cells’ genomes, transcriptomes, proteomes, and metabolomes, as well as intratumoral immune niches, we strongly advocate that microbes must be considered members of any multi-omic clonal evolution model. However, as distinct agents from cancer cells with separate genetic material that can face discordant selection pressure(s) from the cancer genome (e.g., antibiotic therapy for bacteria, targeted kinase therapies for cancer cells), cancer-resident microbes cannot merely be added as another “-ome.” This non-sterility of tumors further violates fundamental assumptions of clonal evolution models that require cells within a clonal type to be homogeneous, since microbes can heterogeneously infect clonal member cells, causing local divergences in cell fitness (e.g., chemotherapy-degrading microbes in pancreatic adenocarcinoma). Studies examining cancer microbiota roles have not yet seriously considered their own clonality or downstream impacts on cancer cell clonality. Thus, there is a theoretical gap between the cancer microbiota and clonal evolution modeling that must be bridged, and this work proposes several key considerations towards establishing such a revised framework for multispecies cancer clonality. In doing so, this talk will stress the impact of microbial mechanisms on local and distal immunomodulation along with their effects on cancer immunoediting and immunotherapy efficacy.