title: p38α negatively regulates survival and malignant selection of transformed bronchioalveolar stem cells.
abstract: Lung cancer is the cause of most cancer-related deaths in the Western world. Non-small cell lung cancer accounts for almost 80% of all lung cancers, and 50% of this type are adenocarcinomas. The cellular and molecular origin of this type of lung cancer remains elusive and the mechanisms are poorly known. It is known that K-Ras mutations appear in 25-30% of lung adenocarcinomas and it is the best known single mutation that can be related to lung cancers. Recently, it has been suggested that a putative population of mouse bronchioalveolar stem cells could be considered as the cell of origin of adenocarcinomas. These cells are expanded in the early stages of lung tumorigenesis. We have isolated a population of mouse bronchioalveolar stem cells and induced their transformation by oncogenic K-RasG12. Different approaches have shown that an intracellular network linking the p38α MAPK and the PI3K-Pdk1 pathways is involved in regulating the survival and malignant progression of the transformed cells. Absence of p38α catalytic activity leads to further Pdk1 activation (independent of Akt and Erk activity), enhancing the survival and proliferation of the more malignant lung cancer cells. This specifically selects high Sca-1/Sox9 cells that harbour a stronger colonizing potential, as they maintain their capacity to produce secondary tumors after serial transplantations.
authors.affiliation: CSCR (Wellcome Trust Centre for Stem Cell Research), Cambridge, United Kingdom.
authors.forename: Edwige
authors.initials: E
authors.lastname: Voisset
authors.forename: Feride
authors.initials: F
authors.lastname: Oeztuerk-Winder
authors.forename: Edgar-Josue
authors.initials: EJ
authors.lastname: Ruiz
authors.forename: Juan-Jose
authors.initials: JJ
authors.lastname: Ventura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D048308:Mitogen-Activated Protein Kinase 14; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018631:ras Proteins; C074650:Ly6a protein, mouse; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse