Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer [VCaP_EnzaResistant_9817-HYW]
Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF.  Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer. Overall design: For cells treated with recombinant proteins: Cells were plated in triplicate in 6 well plates (500,000-750,000 cells/well) and allowed to adhere for 24-48 hours. Cells were starved in serum and calcium-free media (Vanderbilt Cell Culture Core) for 6-12 hours prior to addition of recombinant proteins. Total RNA was extracted from cells after 0, 12, or 24 hrs of treatment. For drug resistant cells: Cells were plated in triplicates in T25 flasks, cultured to a confluency of ~70%, and harvested for total RNA extraction.