Bone Morphogenetic Protein (BMP) signaling upregulates expression of ID1 and ID3 in pancreatitis and pancreatic ductal adenocarcinoma

Abstract

Identification of biological modulators of pancreatic ductal adenocarcinoma (PDAC) initiation and progression are of critical importance as it remains one of the deadliest cancers. We have previously shown that ID1 and ID3 are highly expressed in human PDAC and function to repress expression of E47 target genes involved in acinar cell differentiation and quiescence. More recently, mining of large bulk RNA-seq and single-cell RNA-seq (scRNA-seq) datasets has associated high expression of ID1 with poor PDAC patient survival. Here, we report that BMP2 signaling in human PDAC cells upregulates expression of ID1 and ID3 while treatment with Noggin, an endogenous BMP antagonist, or with DMH1, a selective inhibitor of the BMP receptor, ALK2, reduced expression of ID1/ID3. BMP signaling, working via the canonical pathway involving phosphorylation of SMAD1/5/9 (pSMAD1/5/9), was increased by exogenous BMP2 but blocked by DMH1. Based on immunohistochemical and scRNA-seq analyses, upregulation of BMP signaling and ID1/ID3 also occurs in murine models of pre-neoplastic lesions (KC mice) and pancreatitis induced by the cholecystokinin analog caerulein. Moreover, we demonstrate that BMP dependent ID1/ID3 expression occurs in a non-transformed human ductal cell line. Strikingly, even short term caerulein treatment promoted BMP signaling and ID1/ID3 expression in a rat exocrine cell line, consistent with a direct link between inflammation of the exocrine pancreas and BMP/ID signaling. Together, the data suggest that BMP signaling through pSMAD1/5/9 to ID1 and ID3 occurs early in pancreas pathogenesis and that pancreatic cancer cells remain addicted to this important signaling circuit. Future exploration of druggable targets within this pathway could be of therapeutic benefit in the treatment of pancreatitis and PDAC.