title: Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways.
abstract: The tumor suppressor Lkb1/STK11/Par-4 is a key regulator of cellular energy, proliferation, and polarity, yet its mechanisms of action remain poorly defined. We generated mice harboring a mutant Lkb1 knockin allele that allows for rapid inhibition of Lkb1 kinase. Culturing embryonic tissues, we show that acute loss of kinase activity perturbs epithelial morphogenesis without affecting cell polarity. In pancreas, cystic structures developed rapidly after Lkb1 inhibition. In lung, inhibition resulted in cell-autonomous branching defects. Although the lung phenotype was rescued by an activator of the Lkb1 target adenosine monophosphate-activated kinase (AMPK), pancreatic cyst development was independent of AMPK signaling. Remarkably, the pancreatic phenotype evolved to resemble precancerous lesions, demonstrating that loss of Lkb1 was sufficient to drive the initial steps of carcinogenesis ex vivo. A similar phenotype was induced by expression of mutant K-Ras with p16/p19 deletion. Combining culture of embryonic tissues with genetic manipulation and chemical genetics thus provides a powerful approach to unraveling developmental programs and understanding cancer initiation.
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lo
authors.forename: Geraldine
authors.initials: G
authors.lastname: Strasser
authors.forename: Meredith
authors.initials: M
authors.lastname: Sagolla
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.forename: Melissa
authors.initials: M
authors.lastname: Junttila
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
mesh_terms: D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds; D016764:Cell Polarity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004285:Dogs; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D038081:Organogenesis; D010179:Pancreas / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D010181:Pancreatic Cyst / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology; D059008:Time-Lapse Imaging; D046509:Tissue Culture Techniques
chemical_list: D001713:Biphenyl Compounds; D020536:Enzyme Activators; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile