Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-β signal activation in pancreatic ductal adenocarcinoma

• DOI: 10.1016/j.tranon.2022.101533
• Publication Date: 2022-09-15T02:27:08Z
• Authors: Kazuki Matsumura; Hiromitsu Hayashi; Norio Uemura; Yoko Ogata; Liu Zhao; Hiroki Sato; Yuta Shiraishi; Hideyuki Kuroki; Fumimasa Kitamura; Takayoshi Kaida; Takaaki Higashi; Shigeki Nakagawa; Kosuke Mima; Katsunori Imai; Yo-ichi Yamashita; Hideo Baba
• Keywords: Thrombospondin 1; Tumor progression

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 known as suppressor in several types of cancers including PDAC, loss triggers accelerated cell invasiveness metastatic potential. The thrombospondin-1 (TSP-1) can act major activator latent transforming growth factor-β (TGF-β) vivo. However, the roles TSP-1 mediator TGF-β signal activation during PDAC progression have not yet been addressed. aim to elucidate biological role progression.High substrate stiffness stimulated expression CAFs, knockdown inhibited proliferation with suppressed profibrogenic activated stroma-related gene expressions CAFs. Paracrine treatment for cells promoted epithelial mesenchymal transition (EMT) signals such phosphorylated Akt Smad2/3 expressions. Surprisingly, DPC4 (Smad4 gene) induced overexpression cells. Interestingly, also downregulation enhanced vitro Treatment LSKL peptide, which antagonizes TSP-1-mediated activation, attenuated proliferation, migration chemoresistance apoptosis cells.TSP-1 derived from CAFs stimulates cancer accelerates malignant behavior PDAC. could be novel therapeutic target, only stiff stroma, but