MUC1-C dictates neuroendocrine lineage specification in pancreatic ductal adenocarcinomas. (17th October 2021)

• Record Type: Journal Article
• Authors: Luan, Zhou; Morimoto, Yoshihiro; Fushimi, Atsushi; Yamashita, Nami; Suo, Wenhao; Bhattacharya, Atrayee; Hagiwara, Masayuki; Jin, Caining; Kufe, Donald
• Is Part Of: Carcinogenesis. Volume 43:Number 1(2022)
• Page Start: 67
• Page End: 76
• Publication Date: 2021-10-17
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgab097
• Languages: English
• ISSNs: 0143-3334

Abstract

Abstract: Pancreatic ductal adenocarcinomas (PDAC) and poorly differentiated pancreatic neuroendocrine (NE) carcinomas are KRAS mutant malignancies with a potential common cell of origin. PDAC ductal, but not NE, lineage traits have been associated with cell-intrinsic activation of interferon (IFN) pathways. The present studies demonstrate that the MUC1 C-terminal subunit (MUC1-C), which evolved to protect mammalian epithelia from loss of homeostasis, is aberrantly overexpressed in KRAS mutant PDAC tumors and cell lines. We show that MUC1-C is necessary for activation of the type I and II IFN pathways and for expression of the Yamanaka OCT4, SOX2, KLF4 and MYC (OSKM) pluripotency factors. Our results demonstrate that MUC1-C integrates IFN signaling and pluripotency with NE dedifferentiation by forming a complex with MYC and driving the (i) achaete-scute homolog 1 and BRN2/POU3F2 neural, and (ii) NOTCH1/2 stemness transcription factors. Of translational relevance, targeting MUC1-C genetically and pharmacologically in PDAC cells (i) suppresses OSKM, NE dedifferentiation and NOTCH1/2, and (ii) inhibits self-renewal capacity and tumorigenicity. In PDAC tumors, we show that MUC1 significantly associates with activation of IFN signaling, MYC and NOTCH, and that upregulation of the MUC1-C → MYC pathway confers a poor prognosis. These findings indicate that MUC1-C dictates PDAC NE lineage specification and is a potential target for the treatment of recalcitrant pancreatic carcinomas with NE dedifferentiation. Abstract : Our results demonstrate that MUC1-C drives PDAC progression by integrating induction of neuroendocrine (NE) dedifferentiation with self-renewal capacity and tumorigenicity, in support of MUC1-C as a druggable target for the treatment of poorly differentiated pancreatic NE carcinomas.