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

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

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

Nabeel Bardeesy,Kuang-Hung Cheng,Justin H Berger,Gerald C Chu,Jessica Pahler,Peter Olson,Aram F Hezel,James Horner,Gregory Y Lauwers,Douglas Hanahan,Ronald A DePinho,

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.

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

N Bardeesy,KH Cheng,JH Berger,GC Chu,J Pahler,P Olson,AF Hezel,J Horner,GY Lauwers,D Hanahan,RA DePinho,

For similar proteins: cell cycle proteins: tumor suppressor protein p14arf research abstracts see: proteins: cell cycle proteins: tumor suppressor protein p14arf research

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Genes & development

VOLUME: 20

Page Numbers: 3130-46

Journal Abbreviation: Genes Dev.

ISSN: 0890-9369

DAY: 15

MONTH: Nov

YEAR: 2006

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 8711660

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

KEYWORDS: Tumor Suppressor Protein p14ARF

MESH TERMS: metabolism

Chemical & Substance for Abstract: Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Information

Substance Name: Tumor Suppressor Protein p14ARF

Registry Number: 0

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

AFFILIATION: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. nelbardeesy@partners.org

Country: United States

AGENCY: United States NCI

GRANT: P01 CA117969-01

ACRONYM: CA

MEDLINETA: Genes Dev

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