Extracellular Domain Shedding of TROP2 Activates EGFR Signaling to Drive Prostate Cancer Metastasis

Metastasis is the main cause of prostate cancer-associated deaths, highlighting the urgent need to determine the mechanisms underlying prostate cancer progression. TROP2 (also known as TACSTD2) is an oncogenic transmembrane surface protein that is highly expressed in metastatic prostate cancer. Naturally occurring cleavage of TROP2 leads to a release of the TROP2 extracellular domain (TECD) into the extracellular environment. In this study, we identified an important functional role of TECD in prostate cancer metastasis. TECD was detectable in media from prostate cancer cells and serum from patients with clinically significant prostate cancer. While shed TECD did not affect prostate cancer cell proliferation and tumor growth, it increased cell migration and invasion in vitro and promoted metastatic colonization and spontaneous metastasis in vivo. TECD interactome and proteomic studies revealed that TECD binds to EGFR and that shed TECD modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. Furthermore, elevated shed TECD increased EGFR phosphorylation, resulting in activation of the EGFR-PI3K-AKT-mTOR pathway in prostate cancer. EGFR inhibitors suppressed the invasive ability of prostate cancer cells driven by TECD overexpression, further supporting the key role of EGFR in TECD-mediated prostate cancer progression. This study uncovers a function of TECD in driving prostate cancer progression and provides mechanistic insights into TECD signaling through EGFR.