Tumor-stroma TGF-β1-THBS2 feedback circuit drives pancreatic ductal adenocarcinoma progression via integrin α
- Resource Type
- Authors
- Peng, Nan; Xiu, Dong; Xiaofeng, Bai; Haizhen, Lu; Fang, Liu; Yulin, Sun; Xiaohang, Zhao
- Source
- Cancer letters. 528
- Subject
- Male
MAP Kinase Signaling System
Mice, Nude
Adenocarcinoma
Integrin alphaVbeta3
Pancreatic Neoplasms
Transforming Growth Factor beta1
Mice
Cell Line, Tumor
Disease Progression
Tumor Microenvironment
Animals
Humans
Female
Carcinoma, Pancreatic Ductal
Cell Proliferation
- Language
- ISSN
- 1872-7980
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-β1 activated CAFs to induce THBS2 expression via the p-Smad2/3 pathway. Consequently, CAF-derived THBS2 bound to the membrane receptors integrin α