Role of SCAP in regulation of pancreatic homeostasis, pancreatitis, and tumorigenesis.

Levels of pancreatic ductal adenocarcinoma (PDAC) are increasing, with epidemiological studies nominating obesity, altered cholesterol metabolism, and elevated lipids as risk factors. In prior studies, we determined that elevated expression of sterol regulatory element binding protein 2 (SREBP2), a transcription factor directing lipid biosynthesis, promoted epithelial-mesenchymal transition and aggressive tumorigenesis in the KPC (LSL-KrasG12D;Trp53f/f;Pdx1-Cre) mouse model of PDAC. We analyzed the consequences of deleting SCAP, a scaffolding protein required for SREBP activation, in KPC mice. Unexpectedly tumorigenesis in KPCS mice was significantly accelerated, with a preponderance of sarcomatoid carcinomas. To better understand SCAP action, we analyzed loss of pancreatic SCAP in isolation in ScapΔpanc (Pdx1-Cre;Scapf/f) mice. Pancreata of ScapΔpanc mice had rapid progressive loss of acinar cells, acinar-ductal metaplasia (ADM), infiltration of adipose cells, increased fibrosis, and infiltration of immune cells, indicative of chronic pancreatitis. Single cell RNA sequencing indicated that loss of SCAP suppressed SREBP-dependent transcriptional programs in endocrine and exocrine precursors, but was associated with enhanced SREBP2 activity in fibroblastic populations, compatible with formation of a pro-tumorigenic tumor microenvironment. Together, these results implicate lipid metabolism via SCAP-SREBP signaling as an important metabolic regulator of acinar-ductal differentiation and pancreatic carcinogenesis.