TROP2 promotes bone metastasis of colorectal cancer through interaction with the fibronectin-integrin axis

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. Bone metastasis, which occurs in advanced cancer, causes severe damage and accelerates patient death. TROP2, encoded by the TACSTD2 gene, is highly expressed in multiple types of cancer and is associated with tumor proliferation, invasion and metastasis. However, the role of TROP2 in CRC is unclear. METHODS: TROP2 expression was detected in tumor tissues of CRC patients with or without bone metastases, as well as CRC cell lines. The functional role of TROP2 on CRC cells was validated by in vitro cell culture models and in vivo mouse experiments. Comparative proteomics was used to discover the interactome of TROP2, and later confirmed by immunoprecipitation and immunofluorescent studies. The therapeutic role of TROP2-targeted agent in CRC was verified by intratibial injection mouse models. RESULTS: TROP2 was highly expressed in the tumor tissues of CRC patients, with largely negative expression in the normal counterparts. CRC patients with bone metastasis had even higher TROP2 expression in the tumors than those with primary carcinoma only. We demonstrated that TROP2 promoted the proliferation and migration of CRC cells by in vitro and in vivo experiments, and the pro-invasive and pro-adhesive effects of TROP2 in CRC cells could be enhanced by co-culturing with bone marrow mesenchymal stem cells (BMSCs). Mechanistically, we validated that TROP2 was able to interact with fibronectin (FN) expressed by BMSCs, which increased the expressions of α5, αV, and β3 integrin subunits and facilitated the expression of integrin-linked kinase (ILK) on CRC cells. This interaction was required for the downstream activation of PI3K-Akt signaling and the CRC cell adhesion to BMSCs. Furthermore, intratibial injection mouse experiments verified that TROP2 promoted the colonization of CRC cells in bone marrow, and the combination of the TROP2-targeted antibody-drug conjugate, Sacituzumab Govitecan, and anti-integrin α5β1 monoclonal antibody, Volociximab, was effective in inhibiting bone colonization of CRC cells. CONCLUSION: TROP2 promotes CRC bone metastasis by interacting with bone marrow-derived FN-integrin axis. Through its adhesive function, TROP2 may coordinate with the specialized bone niche to facilitate metastatic colonization and establish a permissive environment for stromal-tumor interactions. Targeting this axis offers a promising therapeutic strategy for managing bone metastasis in CRC and potentially other TROP2-overexpressing malignancies.