title: Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung.
abstract: Senescence in cancer cells acts as a tumor suppressor, whereas in fibroblasts enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of cancer subtypes. However, the presence of senescent TAFs in lung cancer remains undefined. We examined senescence in TAFs from primary lung cancer and paired control fibroblasts from unaffected tissue in three major histologic subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Three independent senescence markers (senescence-associated beta-galactosidase, permanent growth arrest and spreading) were consistently observed in cultured LCC-TAFs only, revealing a selective premature senescence. Intriguingly, SCC-TAFs exhibited a poor growth response in the absence of senescence markers, indicating a dysfunctional phenotype rather than senescence. Co-culturing normal fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to render fibroblasts senescent through oxidative stress, indicating that senescence in LCC-TAFs is driven by heterotypic signaling. In addition, senescent fibroblasts provided selective growth and invasive advantages to LCC cells in culture compared to normal fibroblasts. Likewise, senescent fibroblasts enhanced tumor growth and lung dissemination of tumor cells when co-injected with LCC cells in nude mice beyond the effects induced by control fibroblasts. These results define the subtype-specific aberrant phenotypes of lung TAFs, thereby challenging the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless of their subtype. Importantly, because LCC often distinguishes itself in the clinic by its aggressive nature, we argue that senescent TAFs may contribute to the selective aggressive behavior of LCC tumors.
authors.affiliation: Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lugo
authors.affiliation: Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gabasa
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori INT, Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Andriani
authors.affiliation: Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain.|Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Puig
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori INT, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: Anatomopathology Unit, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Ramírez
authors.affiliation: Thoracic Surgery Unit, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Gómez-Caro
authors.affiliation: Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
authors.affiliation: Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Fuster
authors.affiliation: Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Almendros
authors.affiliation: Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Gascón
authors.affiliation: Buck Institute for Age Research, Novato, CA, US.
authors.forename: Albert
authors.initials: A
authors.lastname: Davalos
authors.affiliation: Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Reguart
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori INT, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.affiliation: Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain.|CIBER de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alcaraz
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D016922:Cellular Senescence; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D018384:Oxidative Stress; D019899:Paracrine Communication; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D059016:Tumor Microenvironment; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D001616:beta-Galactosidase
keywords: cancer associated fibroblast; invasion; large cell carcinoma; lung cancer; senescence