Tumor-stroma TGF-β1-THBS2 feedback circuit drives pancreatic ductal adenocarcinoma progression via integrin αvβ3/CD36-mediated activation of the MAPK pathway

The pancreatic ductal adenocarcinoma (PDAC) microenvironment contains dense desmoplastic stroma dominated by cancer-associated fibroblasts (CAFs) and is crucial to cancer development and progression. Several studies have revealed that thrombospondin 2 (THBS2) is a valuable serological-marker in PDAC. However, the detailed mechanism of the cancer-stroma interactome remains unclear. Here we showed that elevated THBS2 expression in PDAC was predominantly restricted to stroma and correlated with tumor progression and poor prognosis by quantitative proteomics and immunohistochemistry analyses. RNA in situ hybridization confirmed that CAFs but not neoplastic cells expressed THBS2 in precancerous lesions and its levels gradually increased with disease progression in genetically engineered mouse models. Mechanistically, cancer cell-secreted TGF-beta 1 activated CAFs to induce THBS2 expression via the p-Smad2/3 pathway. Consequently, CAF-derived THBS2 bound to the membrane receptors integrin alpha(v)beta(3)/CD36 and activated the MAPK pathway in PDAC cells to promote tumor growth and adhesion in vitro and in vivo. Inhibition of integrin alpha(v)beta(3), CD36, MEK and JNK rescued THBS2-induced malignant phenotypes. In conclusion, the TGF-beta 1-THBS2-integrin alpha(v)beta(3)/CD36-MAPK cascade forms a complex feedback circuit to mediate reciprocal interactions of pancreatic cancer cells-CAFs. THBS2 may act as a novel therapeutic-target to block the cancer-stroma communication.

Automated summary

The cancer-associated fibroblasts (CAFs) and thrombospondin 2 (THBS2) in the microenvironment of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor development and prognosis. It has been found that elevated THBS2 expression in PDAC is mainly located in the stroma and is associated with tumor progression and poor prognosis. The study also revealed that cancer cell-secreted TGF-beta 1 activates CAFs to induce THBS2 expression, which then promotes tumor growth and adhesion in PDAC cells.