Abstract P4-03-06: Microenvironmental control of breast cancer subtype elicited by paracrine growth factors signaling

Abstract

Abstract During cancer progression from an indolent stage to a clinically manifested disease, the surrounding microenvironment co-evolves into an activated state through continuous and dynamic paracrine communication between all constituent cell types that collectively sustain malignant growth. Hence, from a therapeutic perspective, tumors must be regarded as multi-cellular organs. Mesenchymal cells are highly plastic entities. Normal fibroblasts are described to counteract tumorigenesis by repressing cancer initiation. However, co-evolution of the malignant epithelium and its underlying stroma instigates activation of cancer-associated fibroblasts (CAFs) into a phenotype endorsing most, if not all, hallmarks of cancer progression. Through translational studies using breast cancer patient cohorts, genetically engineered mouse models (including patient derived xenografts), and single-cell RNA sequencing, we delineate a previously unappreciated role for CAFs as determinants of breast cancer prognosis and treatment response through specification of the molecular subtype of breast cancer. Expression of paracrine growth factors mediating malignant cell-CAF crosstalk in breast cancer was found to be associated with a hormone receptor-negative state. Genetic targeting of the signaling networks governing the interactions between tumor cells and CAFs confirmed their functional importance by prompting a delay in tumor growth, impaired extra-cellular matrix deposition and reduced angiogenesis. Importantly, our work holds therapeutic implications, as genetic or therapeutic targeting of CAF subsets resulted in conversion of basal-like/triple-negative breast tumors into a luminal state that conferred sensitivity to endocrine therapy in previously impervious tumors. Additionally, to mechanistically explore the heterogeneity of mesenchymal cells in breast tumors, we have made use of single cell RNA sequencing of isolated CAFs as a guide to divide cells into transcriptionally similar groups. Distinct clusters of different CAF subtypes were identified and found to denote diverse functions in the tumor microenvironment. In conclusion, therapeutic targeting of functional subsets of CAFs may be exploited as a refined strategy to improve patient benefit from established treatments by impinging on the stimulatory crosstalk between CAFs and their surrounding malignant microenvironment. Citation Format: Bocci M, Bartoschek M, Pietras K. Microenvironmental control of breast cancer subtype elicited by paracrine growth factors signaling [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-06.