Identification of Asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer

Abstract

Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a distinct subtype of CAF that express a four-gene signature (CHTRC1, ASPN, FAP and ENG), termed CAFÉ CAF, that are enriched in the TME of aggressive prostate cancer and associated with worse patient outcomes. Furthermore, we identify a novel paracrine mechanism in which one of the CAFÉ CAF markers, ASPN, is secreted by CAF and activates ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data supports that ASPN binds directly to the ligand binding domain of HER3 to induce HER2/HER3 heterodimerization and activation of downstream signaling pathways including Phosphoinositide 3-kinase (PI3K), Mitogen-activated protein kinase (MAPK), and calcium signaling. Genetic and therapeutic inhibition of HER2 and/or HER3 ablate ASPN-induced signaling and migration. Clinically, ASPN is detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target either HER2 (trastuzumab deruxtecan) or HER3 (patritumab deruxtecan) significantly diminish prostate cancer cell growth in vitro as well as restrict tumor size in vivo, despite ASPN in the TME. Collectively, these findings indicate ASPN functions as a novel HER3 ligand to induce cellular migration, and inhibition of this pathway with either anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer (mCRPC) that expresses HER2 or HER3.