title: Oncogenic Effects of High MAPK Activity in Colorectal Cancer Mark Progenitor Cells and Persist Irrespective of RAS Mutations.
abstract: About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling, which promotes tumor invasion and progression. Here, we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models, and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells. In KRAS-mutant colon cancer, regulation of MAPK signaling was preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marked a progenitor cell compartment of growth-fueling colon cancer cellsin vivoOur results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer.Cancer Res; 77(7); 1763-74. ©2017 AACR.
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Blaj
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.
authors.forename: Eva Marina
authors.initials: EM
authors.lastname: Schmidt
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lamprecht
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany. david.horst@med.uni-muenchen.de.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Horst
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: C117307:KRAS protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)