Stroma-Mediated Breast Cancer Cell Proliferation Indirectly Drives Chemoresistance by Accelerating Tumor Recovery between Chemotherapy Cycles

Abstract

The ability of tumors to survive therapy reflects both cell-intrinsic To evaluate this hypothesis, a spatial agent–based model of stroma and microenvironmental mechanisms. Across many cancers, impact on proliferation/death dynamics was developed that was including triple-negative breast cancer (TNBC), a high stroma/tuquantitatively parameterized using inferences from histologic analmor ratio correlates with poor survival. In many contexts, this yses and experimental studies. The model demonstrated that the correlation can be explained by the direct reduction of therapy observed enhancement of tumor cell proliferation within stroma-sensitivity induced by stroma-produced paracrine factors. We proximal niches could enable tumors to avoid elimination over sought to explore whether this direct effect contributes to the link multiple chemotherapy cycles. Therefore, this study supports the between stroma and poor responses to chemotherapies. In vitro existence of an indirect mechanism of environment-mediated studies with panels of TNBC cell line models and stromal isolates chemoresistance that might contribute to the negative correlation failed to detect a direct modulation of chemoresistance. At the same between stromal content and poor therapy outcomes. time, consistent with prior studies, fibroblast-produced secreted factors stimulated treatment-independent enhancement of tumor Significance: Integration of experimental research with mathecell proliferation. Spatial analyses indicated that proximity to stroma matical modeling reveals an indirect microenvironmental chemoreis often associated with enhanced tumor cell proliferation in vivo. sistance mechanism by which stromal cells stimulate breast cancer These observations suggested an indirect link between stroma and cell proliferation and highlights the importance of consideration of chemoresistance, where stroma-augmented proliferation potentiproliferation/death dynamics. ates the recovery of residual tumors between chemotherapy cycles. See related commentary by Wall and Echeverria, p. 3667