Abstract LB223: The molecular landscape of injury-induced mammary epithelial cell fate switching

Abstract The most aggressive cancers, such as triple negative basal-like breast cancer (TNBC), have high intratumoral heterogeneity that is often attributed to cell state reprogramming and contributes to cancer progression, treatment resistance, and ultimately cancer death. Tissue injury and microenvironmental changes can cause adult differentiated cells to acquire a plastic “developmentally unstable hybrid cell state” (DUHCS) enabling transdifferentiation into other cell types to effect repair. Yet, the relevant mechanisms that enable cell state reprogramming to arise remain under-explored. Here, we used CRISPR mediated homologous recombination to generate mice in which the mammary basal and luminal cells could be distinguished by their expression of Krt14-mClover-NLS or Krt18-tdTomato-NLS, respectively. We used this novel system to identify mammary epithelial cells undergoing cell state transitions in real time. Using a transplantation paradigm, we found that transplanted basal cells rapidly exhibited a DUHCS resembling mammary embryonic progenitors expressing Sox11, a tightly regulated differentiation factor shut off before birth. We discovered that Sox11 is also expressed in many murine models of TNBC and in single cell transcriptomes from untreated human BRCA1 mutant TNBCs. This suggests that Sox11-expressing cells might be developmentally plastic intermediates in TNBC malignant progression. In a preliminary cohort of patient-derived xenografts from TNBC patients diagnosed at different stages, we detected SOX11-expressing cells in earlier but not in advanced stages. Re-expression of Sox11 in TNBC is consistent with TNBCs being transcriptomically related to fetal mammary stem cells and p53 dysfunction resulting in enhanced cellular plasticity. Taken together, these studies highlight a role for mammary epithelial cell state reprogramming in early breast tumorigenesis, and reveals actionable steps to mitigate tumor heterogeneity by halting tumor progression. Citation Format: Queralt Vallmajó Martín, Nikki K. Lytle, Divya Murali, Sumana Srinivasan, Zhibo Ma, Kavitha Mukund, Christopher Dravis, Liliana Zamora, Ana Peterson, Galina Khramtsova, Funmi Olopade, Shankar Subramaniam, Geoffrey M. Wahl. The molecular landscape of injury-induced mammary epithelial cell fate switching abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB223.