Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY/ABSTRACT Intratumor heterogeneity (ITH) and clonal evolution pose tremendous challenges in designing effective and durable cancer therapies. This is highly relevant for PCa, a prime example of a highly heterogenous disease where fluctuating cellular subpopulations (“clones”) with distinct mutational and phenotypic profiles can coexist and evolve independently, diversify and compete during the course of the disease. The majority of ITH studies centers on genetic determinants, while non-genetic variability such as due to spatial clonal distributions and interactions of tumor subpopulations with each other and with the immune TME remain poorly understood. These mechanisms are multifaceted, context-dependent and difficult to investigate experimentally in vivo. However, these complex interactions might hold powerful anti-tumor interventions. For instance, mechanisms of elimination of “loser” cells/clones could be exploited to lower overall tumor fitness and new targeted therapies could be developed to counteract the factors that enable clonal dominance. We recently generated new reductionist models of ITH that reflect, at least in part, the clonal fitness diversity of human PCa. By incorporating multicolor lineage tracing in mouse models, longitudinal organoid studies and single cell transcriptomics, we showed that less severe models accommodate the coexistence of multiple growing tumor subpopulations. In contrast, aggressive tumors exhibit a drastic and rapid clonal reduction, emergence of larger dominant populations as slower-growing populations are out-competed by fast-growing ones in vivo and in vitro, and massive TME remodeling. In the same time, some minor populations persist and might serve as a reservoir for drug-resistant clones. Moreover, the minor populations have distinct immunoediting molecular signatures marked by increased expression of Cxcl9/Cxcl11 and MHC class II members. We hypothesize that direct competition mechanisms between dominant and minor clones within specialized TME niches coupled with fitness effects of the immune system on clonal expansions determine the ITH in PCa. The goal of this proposal is to identify molecular mechanisms and cellular contexts underlying clonal interactions with each other and with TME by pursuing 1) Functional mapping of tumor competitive landscapes in mouse models of PCa by spatial transcriptomic analyses and 2) Elucidate the role of Cxcl9/11 in reducing the fitness potential of minor clones by novel competition-chemotaxis and T-cell infiltration organoid assays and in vivo immunomodulatory interventions. Results from these studies will not only greatly expand our understanding of population-level interactions in tumors, but also uncover new targetable immunoediting mechanisms that operate at clonal level in driving clonal diversification and selection with impact on preventing progression to advanced disease and drug resistance.
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