Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: Implications for exocrine/endocrine signaling

•Mechanisms of islet impairment caused by CF exocrine pancreatic insufficiency are unknown.•Loss of CFTR alters the CF ductal epithelial secretome and proteome.•Alterations in CF ductal epithelial secretions implicate TGFβ, WNT, and BMP signaling.•IGFBP7 secretion by CF ductal epithelia is reduced and IGFBP7 alters glucose-stimulated islet insulin secretion.•Loss of ductal cell CFTR may impact islet function via paracrine signals.•TGFβ, PDX1, and PTEN/AKT signaling were upstream regulators implicated in the CF ductal phenotype. Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals. We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion. The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFβ, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFβ, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126. These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.