title: Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression.
abstract: Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: da Silva-Diz
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Simón-Extremera
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Adrià
authors.initials: A
authors.lastname: Bernat-Peguera
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Jana
authors.initials: J
authors.lastname: de Sostoa
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Urpí
authors.affiliation: Pathology Service, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Penín
authors.affiliation: Plastic Surgery Unit, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
authors.forename: Diana Pérez
authors.initials: DP
authors.lastname: Sidelnikova
authors.affiliation: Plastic Surgery Unit, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Bermejo
authors.affiliation: Plastic Surgery Unit, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
authors.forename: Joan Maria
authors.initials: JM
authors.lastname: Viñals
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Annie
authors.initials: A
authors.lastname: Rodolosse
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: González-Suárez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Antonio Gómez
authors.initials: AG
authors.lastname: Moruno
authors.affiliation: Laboratory of Translational Research, Catalan Institute of Oncology (ICO/IDIBELL), Barcelona, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Pujana
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. Unitat de Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques II, Universitat de Barcelona-IDIBELL, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Laboratory of Translational Research, Catalan Institute of Oncology (ICO/IDIBELL), Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Laboratory of Translational Research, Catalan Institute of Oncology (ICO/IDIBELL), Barcelona, Spain. Unitat de Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques II, Universitat de Barcelona-IDIBELL, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. p.munoz@idibell.cat.
authors.forename: Purificación
authors.initials: P
authors.lastname: Muñoz
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000556:secondary; D019070:Cell Lineage; D049109:Cell Proliferation; D018450:Disease Progression; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D051379:Mice; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology*
chemical_list: D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D066246:ErbB Receptors