Abstract B64: Sox10 drives tumor progression in breast cancer by reprogramming mammary tumor cells into a state of plasticity resembling primitive neural crest cells

Abstract

Abstract Many foundational features of tumor malignancy such as tumor initiation, tumor heterogeneity, therapeutic resistance, and metastasis are driven through dysregulated cell plasticity. Thus, the development of strategies to counter mechanisms of reprogramming in cancer cells is a critical area of need in the field. To address this challenge, we have focused on discovering how cell plasticity is specified in normal mammary development and tissue, and how these processes may be co-opted to drive tumor progression in breast cancer. To facilitate the study of these complex phenomena, we have developed a CRISPR- and tissue engineering-based platform system to rapidly generate de novo, in vivo, mammary glands and mammary tumors that carry any conceivable genomic modification. Here, we have used this system to study the function of Sox10 in breast cancer, as we have previously shown that the transcription factor Sox10 is a critical mammary cell plasticity factor that labels and is functionally required for stem/progenitor activity in normal mammary cells. We now demonstrate that Sox10 is also a major plasticity factor in breast cancer. We find that Sox10 is expressed in both human breast cancer and multiple murine mammary tumor models, and demonstrate critical roles for Sox10 in driving both tumor initiation and progression. Sox10 expression in these tumors correlates with multiple indicators of elevated cell plasticity, which include features of de-differentiation and EMT, specific enrichment of mammary stem/progenitor identity, and expanded lineage potential compared to normal mammary cells. In addition to its role in specifying stem/progenitor activity in mammary cells, Sox10 is also a dominant specifier of neural crest cells, a primitive and highly plastic cell state found only in the early embryo. Strikingly, we find that Sox10+ mammary tumor cells also exhibit transcriptional and epigenetic features of neural crest cells that are not found in normal mammary cells. Collectively, these data reveal that Sox10 is a major plasticity factor that contributes to mammary tumor progression, and demonstrate the remarkable scope of cell state reprogramming that can occur during tumorigenesis when potent plasticity factors are dysregulated. Note: This abstract was not presented at the conference. Citation Format: Christopher Dravis, Geoffrey Wahl. Sox10 drives tumor progression in breast cancer by reprogramming mammary tumor cells into a state of plasticity resembling primitive neural crest cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B64.