The Vitamin D3 Analog Calcipotriol Attenuates Pancreatic Cancer Malignancy via Downregulating Thrombospondin 1 in Pancreatic Stellate Cells

Pancreatic ductal adenocarcinoma (PDAC) exhibits pronounced desmoplasia, primarily attributed to the activation of pancreatic stellate cells (PSCs) from a quiescent state (quiescent PSCs [qPSCs]) to an activated form (activated PSCs [aPSCs]), which facilitates tumor progression and therapeutic resistance. This study investigates the potential of the vitamin D3 (VD) analog calcipotriol (Cal) to modulate this activation process and its impact on PDAC cell malignancy, with a particular focus on the thrombospondin 1/cluster of differentiation 47 (THBS1/CD47) signaling axis. Through analyzing VDR mRNA expression in aPSCs versus PDAC cells, we found that aPSCs are more responsive to VD signaling. Treatment with Cal significantly reduced aPSC activation, as evidenced by decreased α-SMA expression and THBS1 secretion, thereby diminishing stromal support for PDAC cell proliferation, migration, and invasion. These changes were mediated by the inhibition of the THBS1/CD47 axis, highlighting a novel mechanism by which Cal disrupts the supportive tumor microenvironment. Our findings highlight the therapeutic potential of targeting aPSCs with VD analogs in PDAC, suggesting a new direction for treatments that aim to interrupt the desmoplastic reaction and thereby inhibit PDAC progression.