Dicer regulates differentiation and viability during mouse pancreatic cancer initiation.
miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
John P
JP
Morris
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Renee
R
Greer
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Holger A
HA
Russ
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Guido
G
von Figura
Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
Grace E
GE
Kim
Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California, United States of America.
Anke
A
Busch
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America.
Jonghyeob
J
Lee
Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California, United States of America.
Klemens J
KJ
Hertel
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America.
Seung
S
Kim
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Michael
M
McManus
Diabetes Center, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Matthias
M
Hebrok
D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D017353:Gene Deletion; D008679:Metaplasia; D051379:Mice; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics*
D043244:Ribonuclease III; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)