Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer.
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.
Bardeesy
Nabeel
N
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. nelbardeesy@partners.org
Cheng
Kuang-Hung
KH
Berger
Justin H
JH
Chu
Gerald C
GC
Pahler
Jessica
J
Olson
Peter
P
Hezel
Aram F
AF
Horner
James
J
Lauwers
Gregory Y
GY
Hanahan
Douglas
D
DePinho
Ronald A
RA
D000483:Alleles; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018450:Disease Progression; D017353:Gene Deletion; D011905:Genes, ras; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000254:growth & development* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010641:Phenotype; D051901:Smad4 Protein / Q000172:deficiency / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D025803:Tumor Suppressor Protein p14ARF