Background: Obesity and type-2 diabetes mellitus (T2DM) are substantial risk factors for pancreatic ductal adenocarcinoma (PDAC). Both obesity and T2DM are often linked to aberrant insulin processing in β cells and altered liver lipid metabolism. In diet-induced obese (DIO) mice, the Kaufman group reported that depleting CHOP/DDIT3, an endoplasmic reticulum (ER) stress transcription factor in β cells normalizes insulin secretion, improves glycemic control, and prevents liver steatosis. In pilot studies, reduced liver metastasis in β-cell Chop knockout mice intrasplenically injected with mouse PDAC cells (KPC) was associated with upregulated hepatic stearoyl-CoA desaturase 1 (SCD1), a crucial enzyme in monounsaturated fatty acid (MUFA) synthesis. Further, Chop depletion in β cells reduced PDAC development in obese mice with pancreas-specific mutant Kras-G12D expression (Ptf1^Cre/+;Kras^G12D/+, KC mice). Based on these findings, we further explored effects of Chop inhibition in β cells and exocrine pancreatic cells on PDAC progression and metastasis. Methods & Results: We used glucagon-like peptide 1 conjugated antisense oligonucleotides (GLP1-Chop ASO) to knockdown Chop mRNA selectively in β cells of KC mice. This intervention led to reduced pancreatic Insulin and Chop mRNA levels in DIO KC mice fed high-fat diets (HFD), and decreased acinar-ductal-metaplasia, precancerous lesion (PanIN) progression and desmoplasia. GLP1-Chop ASO administration improved glycemic control and diminished liver steatosis. To unravel molecular changes underlying these effects, we performed lipidomics analysis on liver tissues from GLP1-Chop ASO-treated KC mice. Results revealed a shift in the liver lipidome, with an increased MUFA to saturated fatty acid (SFA) ratio, and upregulated SCD1, as observed in β-cell specific Chop knockout mice. Our results associating increased liver SCD1 expression with tumor-inhibitory effects of β Chop deletion challenge previous findings, as SCD1 was implicated in promoting cancer cell proliferation and metastasis. To further confirm the role of CHOP in suppressing PDAC, we ablated Chop expression in exocrine pancreatic cells (Ptf1^Cre/+;Kras^G12D/+;Chop^fl/fl; KC-C). KC-C mice showed significantly less PanIN progression and stromal expansion in pancreas, and higher liver SCD1 expression than KC, further indicating that CHOP plays pivotal roles in both endocrine and exocrine cells in promoting PDAC. Conclusions: Our studies provide novel insights into the complex relationship among ER stress signaling in the endocrine/exocrine pancreas, liver lipid metabolism and PDAC progression and metastasis. CHOP targeting emerges as a promising therapeutic strategy to manage tumor burden and metastasis in PDAC. The specific role of hepatic SCD1 in this context could unveil additional therapeutic avenues to suppress cancer liver metastasis.

Albert-Fred Aquino

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