Abstract B051: Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling

Abstract

Abstract Chromosomal instability (CIN) is an important driver of tumor evolution and metastasis, yet its role in stemness remains unclear. Here, we describe CIN tolerance as a key attribute of stem-like cancer cells. We identified CIN as a critical stress induced during early tumor initiation that may pose a significant barrier limiting the growth of new tumors. While basal CIN levels were not sufficient to distinguish stem from non-stem cell types, CIN was upregulated in early-stage tumors from breast cancer stem cells in an activated signaling state, suggesting these cells could better tolerate this stress. Indeed, stem-like cell lines were more resistant to increased CIN compared to basal-like cells, despite similar baseline levels. Further, the CIN induced during early tumor initiation appears to be transient, as levels diminish in more established disease. Mechanistically, CIN resistance in stem-like cells is mediated by expression of the receptor tyrosine kinase AXL downstream of activated c-Jun stress signaling. Thus, CIN tolerance due to activation of c-Jun/AXL may be a defining feature of stemness, contributing to breast cancer progression. Citation Format: Shahnawaz A Baba, Qi Sun, Samson Mugisha, Shreyas Labhsetwar, Richard Klemke, Jay S Desgrosellier. Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B051.