title: Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH.
abstract: The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2].
authors.forename: Jelena
authors.initials: J
authors.lastname: Urosevic
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institut de Malalties Hemato-Oncològiques, Hospital Clínic de Barcelona-IDIBAPS and CIBER-EHD), 08036 Barcelona, Spain [3].
authors.forename: Xabier
authors.initials: X
authors.lastname: Garcia-Albéniz
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Evarist
authors.initials: E
authors.lastname: Planet
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Real
authors.affiliation: 1] Grup d'Oncogenesi i Antitumorals, Hospital de Sant Pau, 08026 Barcelona, Spain [2] Grup d'Oncogenesi i Antitumorals, Institute of Biomedical Research (IIB Sant Pau), Network Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08026 Barcelona, Spain.
authors.forename: María Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Guiu
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bellmunt
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Gawrzak
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Pavlovic
authors.affiliation: 1] Grup d'Oncogenesi i Antitumorals, Hospital de Sant Pau, 08026 Barcelona, Spain [2] Grup d'Oncogenesi i Antitumorals, Institute of Biomedical Research (IIB Sant Pau), Network Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08026 Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Mangues
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Molecular Partners AG, 8952 Schlieren, Switzerland.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Dolado
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Barriga
authors.affiliation: Institut de Malalties Hemato-Oncològiques, Hospital Clínic de Barcelona-IDIBAPS and CIBER-EHD), 08036 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nadal
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 10065 New York, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Gomis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D044162:Parathyroid Hormone-Related Protein; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins