The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis

Abstract

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.

A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

“…Sox9 is a transcription factor that controls cell-fate decisions during embryonic development and homeostasis of a broad range of adult tissues [62][63][64] . Moreover, in cancer cells, SOX9 inhibits apoptosis and promotes proliferation, invasion, and metastasis [65][66][67] . Interestingly, two recent studies 44,45 have shown that transcriptional upregulation of Sox9 is an early cellular response to renal injury, and Sox9 is essential for repair and recovery post AKI.…”

5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma

“…This is important as unique TE signatures in pre-malignant tissues that contribute to or are predictive of malignant transformation may be useful in the design of early diagnostic or therapeutic strategies (37). To this end, we determined the frequency and types of TEs expressed during pre-malignant (ADM) and malignant (PDAC) stages of pancreatic cancer utilizing an inducible model which restricts the oncogenic alleles Kras G12D and Trp53 R270H to pancreatic, acinar-specific expression through a tamoxifen-inducible Ptfa1-Cre promoter (38,39). Intraperitoneal administration of tamoxifen in 4-5 week old mice consistently results in a steady chronologic progression to PDAC that is equivalent to that observed in humans: ADM > pancreatic intraepithelial neoplasia (PanIN) > PDAC > liver and lung metastases (40).…”

Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer

“…Our previous work indicated ATF3 directly regulated expression of transcription factors involved in ADM [22]. IF for SOX9, which is required for ADM [36, 39], showed limited expression in saline-treated animals, localizing specifically to ductal epithelial cells. As previously reported, SOX9 expression was observed in acinar cells and ADM structures 1 and 7 days following rCIP in WT mice (Figure 3A, B).…”

“…Our laboratory showed ATF3 is required for ADM during acute injury [22] by activating Sox9 (Sry-related high-mobility group box 9) and repressing Mist1 , which maintains the mature acinar cell phenotype [35]. SOX9 and MIST1 are important regulators of ADM, required for [36] or limiting [37] PDAC progression through ADM/pancreatic intraepithelial neoplasia (PanIN) formation, respectively.…”