Boyapati, K. | Search bioRxiv

bioRxiv2021

Pre-neoplastic stromal cells drive BRCA1-mediated breast tumorigenesis

Women with germline mutations in BRCA1 (BRCA1+/mut) have increased risk for developing hereditary breast cancer1, 2. Cancer initiation in BRCA1+/mut is associated with pre-malignant changes in the breast epithelium including altered differentiation3-5, proliferative stress6 and genomic instability7. However, the role of the epithelium- associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here, we show that the pre-malignant stromal niche promotes epithelial proliferation and BRCA1- driven cancer initiation in trans. Using single-cell RNAseq (scRNAseq) analysis of human pre-neoplastic BRCA1+/mut and control breast tissues, we show that stromal cells provide numerous pro-proliferative paracrine signals inducing epithelial proliferation. We identify a subpopulation of pre-cancer associated fibroblasts (pre-CAFs) that produces copious amounts of pro-tumorigenic factors including matrix metalloproteinase 3 (MMP3)8, 9, and promotes BRCA1-driven tumorigenesis in vivo. Our gene-signature analysis and mathematical modeling of epithelial differentiation reveals that stromal-induced proliferation leads to the accumulation of luminal progenitor cells with altered differentiation, and thus contributes to increased breast cancer risk in BRCA1+/mut. Our results demonstrate how alterations in cell-cell communication can induce imbalances in epithelial homeostasis ultimately leading to cancer initiation. We anticipate our results to form the foundation for novel disease monitoring and therapeutic strategies to improve patient management in hereditary breast cancer. For example, pre-CAF specific proteins may serve as biomarkers for pre-cancerous disease initiation to inform whether radical bilateral mastectomy is needed. In addition, MMP inhibitors could be re-indicated for primary cancer prevention treatment in women with high-risk BRCA1 mutations.

cancer biology↗

bioRxiv2020

Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy

The discovery that androgens play an important role in the progression of prostate cancer (PCa) has led to the development of androgen deprivation therapy as a first line of treatment against PCa. However, paradoxical growth inhibition has been observed, both experimentally and clinically, in a subset of PCa upon administration of supraphysiological levels of testosterone (SupraT). Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive PCa cells. This is initiated by induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activates nucleic acid sensors that converge on NF-kappaB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT results in increased migration of cytotoxic immune cells to tumor beds of animal xenografts and patient tumors. Collectively, our findings indicate that SupraT may inhibit a subset of PCa by activating nucleic acid sensors and downstream immune signaling.

cancer biology↗