Downregulation of transforming growth factor-β2 enhances the chemosensitivity to gemcitabine with diminished metastasis in pancreatic cancers

Pancreatic cancer is characterized by high rates of metastasis, recurrence, and chemoresistance, contributing to its poor prognosis. Transforming growth factor-β2 (TGF-β2), a member of the TGF-β family, plays a pivotal role in promoting cancer cell metastasis and mediating chemoresistance, particularly in advanced stages of tumor progression. However, the precise role of TGF-β in chemoresistance and metastasis in pancreatic cancer has not been studied yet. In the current study, we investigated the potential of human TGF-β2 antisense oligonucleotides (TGF-β2i) to enhance the chemosensitivity to gemcitabine in pancreatic cancer, using human pancreatic cancer cell lines (hPCCs; PANC-1, MIA PaCa-2, and AsPC-1), a co-culture model with human pancreatic stellate cells (hPSCs), a cancer-associated fibroblast-integrated pancreatic cancer organoid model (CIPCO), and an orthotopic xenograft mouse model. TGF-β2i decreased cell proliferation, migration, and viability in hPCCs, and its combination with gemcitabine exhibited a synergistic effect in PANC-1 and MIA PaCa-2 cells. Flow cytometry demonstrated a decrease in CD44 +CD24 +EpCAM^High cancer stem-like cell populations following TGF-β2i treatment. In co-culture models, hPSCs-induced enhancement of hPCCs migration was attenuated by TGF-β2i. In the CIPCOs, TGF-β2i suppressed the gemcitabine-induced expression of extracellular matrix components such as COL1A1 and VIM. Furthermore, in an orthotopic mouse model generated by co-inoculating hPCCs and hPSCs into the pancreatic wall, co-treatment of TGF-β2i with gemcitabine significantly delayed tumor growth and metastasis to the liver compared to vehicle control. These findings suggest that TGF-β2i enhances chemosensitivity and suppresses metastatic properties by regulating both tumor-intrinsic and -extrinsic factors, indicating that targeting TGF-β2 could be a promising strategy for managing pancreatic cancer.