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

Authors

• Shiqin Liu
• En-Chi Hsu
• Merve Aslan
• Fernando Garcia-Marques
• Michelle Shen
• Alifiani B Hartono
• Francisco Solano
• Kewei Le
• Hyeonji Hwang
• Chung S Lee
• Abel Bermudez
• Rosalie Nolley
• Donna M Peehl
• James D Brooks
• Michael A Liss
• Sharon J Pitteri
• Tanya Stoyanova

Language

English

Publication Date

12-1-2025

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-24-4855

PMID

40911783

PMCID

PMC12662719

PubMedCentral® Posted Date

11-29-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

UNLABELLED: 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 tumor-associated calcium signal transducer 2) 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. Although 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 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 the 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.

SIGNIFICANCE: Shed extracellular domain of TROP2 binds to and activates EGFR and stimulates the PI3K-AKT-mTOR signaling cascade to promote prostate cancer metastasis, providing potential biomarkers and therapeutic targets.

Keywords

Humans, Male, Prostatic Neoplasms, Cell Adhesion Molecules, ErbB Receptors, Signal Transduction, Antigens, Neoplasm, Animals, Cell Movement, Mice, Cell Line, Tumor, Neoplasm Metastasis, Cell Proliferation, Epithelial-Mesenchymal Transition

Published Open-Access

yes

Recommended Citation

Liu, Shiqin; Hsu, En-Chi; Aslan, Merve; et al., "Extracellular Domain Shedding of TROP2 Activates EGFR Signaling to Drive Prostate Cancer Metastasis" (2025). Faculty, Staff and Student Publications. 4529.
https://digitalcommons.library.tmc.edu/uthmed_docs/4529