Abstract IA15: Normal and cancer stem cells in multistage carcinogenesis

Mouse models of cancer have been instrumental in the development of our understanding of the processes that drive multistage carcinogenesis from the initiation stage to metastasis. In particular, tumors induced in mice by exposure to chemicals that act as mutagens or tumor promoters replicate many of the biologic and genetic features of multistage cancer in human populations. Such models often have a high burden of point mutations and gene copy number changes similar to human tumors of the lung, colon, or skin that are associated with exposure to exogenous environmental agents. These are important features that contribute to tumor heterogeneity—a major cause of drug resistance and poor response to therapy in human cancer patients. The availability of mouse models of tumors with a high mutation burden also offers possibilities for development of immunotherapy approaches that are dependent on expression of novel tumor antigens resulting from carcinogen-induced mutations in tumor DNA. Initiation of chemical carcinogenesis in the mouse is frequently caused by point mutations in genes of the Ras family. The nature of the initiating Ras mutation depends on the carcinogen used, but a similar “mutation signature” is seen throughout the genome of the initiated cell. Tumor cells, however, continually acquire additional new genetic alterations, leading to the emergence of multiple, genetically distinct tumor subclones. By combining the 4-color lineage tracing Confetti mouse with a chemical carcinogenesis model of skin cancer, we have investigated clonal and evolutionary dynamics at every stage of chemical carcinogenesis, from the initiated cell to benign tumors, malignant carcinomas, and ultimately to distant metastases. These studies reveal distinct patterns of clonal evolution at different stages of progression. The growth of subclones within tumors is driven by a stem cell population marked by expression of the Lgr6 gene—a known marker of normal skin stem cells and mediator of Wnt signaling in the epidermis. The use of mouse models for identification of patterns of clonal heterogeneity, and the drivers of clonal growth from cancer stem cells, may offer new possibilities for prevention or treatment of squamous carcinomas. Citation Format: Allan Balmain. Normal and cancer stem cells in multistage carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA15.