Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer.

By N. Bardeesy, Kuang-Hung Cheng, J. Berger, Gerald C. Chu, Jessica C. Pahler, P. Olson, A. Hezel, J. Horner, G. Lauwers, D. Hanahan and 1 more. Genes & Development, 2006

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SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene. Here, using genetically engineered mice, we determined the impact of SMAD4 deficiency on the development of the pancreas and on the initiation and/or progression of PDAC-alone or in combination with PDAC--relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS(G12D) allele, SMAD4 deficiency enabled rapid progression of KRAS(G12D)-initiated neoplasms. While KRAS(G12D) alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS(G12D) and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS(G12D) INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor-beta (TGF-beta) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-beta-induced proliferation and migration. These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, functioning to block the progression of KRAS(G12D)-initiated neoplasms, whereas in a subset of advanced tumors, intact SMAD4 facilitates EMT and TGF-beta-dependent growth.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/951ba64fe129896b1881c92479a7a4ee7c617467

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Citations in the corpus

TGFβ in Cancer (2008, background): “Indeed, ablation of SMAD4 in the mammary gland, liver, or pancreas of mice does not derail the development of the targeted organ even though the disruption of TGFβ family receptors does (Bardeesy et al., 2006; Li et al., 2003; Wang et al., 2005a).”
Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. (2007, background): “Cooperation of K-Ras oncogene expression in various settings with additional mutations, including deletion or inactivation of P53, Ink4a/Arf, Smad4, TGFbR2, or Smad4, as well as activation of Hedgehog signaling, also results in a significant acceleration of tumor development and, in some instances, ”
A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. (2009, background): “Deletion of Smad4 in cooperation with K-ras mutational activation accelerates tumor progression in a mouse model of pancreatic cancer (Bardeesy et al., 2006).”
TGF-β Signaling from Receptors to Smads (2016, neutral): “2008), possibly explaining instances of Smad4-independent gene regulation (Bardeesy et al. 2006).”
A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition (2009, background): “and SMAD4 promotes tumour cell invasion in advanced pancreatic tumour”
Transforming Grown Factor-β Signaling in Immunity and Cancer (2019, neutral): “Exceptions include the development of the pancreas in mice (Bardeesy et al., 2006) and the induction of the master transcription factor SOX4 in pancreatic epithelial progenitors (David et al.”
DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. (2009, background): “Although functional Dpc4 does not appear necessary for TGF- mediated EMT,(29) in mouse models of pancreatic cancer functional Dpc4 has been associated with an undifferentiated phenotype.(34) However, four of seven patients’ carcinomas with anaplastic morphology in this study had loss of Dpc4 immunol”