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Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-ß1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-ß1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs., Peer Reviewed, Postprint (published version)

Gene expression (GE) analyses on blood samples from marathon and half-marathon runners have reported significant impacts on the immune and inflammatory systems. An ultra-marathon trail (UMT) represents a greater effort due to its more testing conditions. For the first time, we report the genome-wide GE profiling in a group of 16 runners participating in an 82 km UMT competition. We quantified their differential GE profile before and after the race using HuGene2.0st microarrays (Affymetrix Inc., California, US). The results obtained were decomposed by means of an independent component analysis (ICA) targeting independent expression modes. We observed significant differences in the expression levels of 5,084 protein coding genes resulting in an overrepresentation of 14% of the human biological pathways from the Kyoto Encyclopedia of Genes and Genomes database. These were mainly clustered on terms related with protein synthesis repression, altered immune system and infectious diseases related mechanisms. In a second analysis, 27 out of the 196 transcriptional regulators (TRs) included in the Open Regulatory Annotation database were overrepresented. Among these TRs, we identified transcription factors from the hypoxia-inducible factors (HIF) family EPAS1 (p< 0.01) and HIF1A (p<0.001), and others jointly described in the gluconeogenesis program such as HNF4 (p< 0.001), EGR1 (p<0.001), CEBPA (p< 0.001) and a highly specific TR, YY1 (p<0.01). The five independent components, obtained from ICA, further revealed a down-regulation of 10 genes distributed in the complex I, III and V from the electron transport chain. This mitochondrial activity reduction is compatible with HIF-1 system activation. The vascular endothelial growth factor (VEGF) pathway, known to be regulated by HIF, also emerged (p<0.05). Additionally, and related to the brain rewarding circuit, the endocannabinoid signalling pathway was overrepresented (p<0.05)., Peer Reviewed, Postprint (published version)

En este artículo se describe el desarrollo de una aplicación web mediante R que permite acceder fácilmente a la información almacenada en una base de datos SQL compleja construida a partir de datos fisiológicos de rendimiento y genéticos de cinco carreras diferentes de ultra-trail, constituyendo una población total de estudio de 170 participantes. Esta aplicación ofrece el acceso interactivo a las diferentes tablas de la base de datos, muestra información estadística y descriptiva de los datos almacenados y permite la visualización de gráficas de evolución y modelos de tendencia construidos a partir de los mismos. El objetivo de esta aplicación es extender el uso de esta información y su análisis a todos los implicados en la investigación en este ámbito, y a largo plazo, desarrollar un repositorio de datos fisiológicos en intervenciones deportivas y permitir la investigación multi-prueba en deporte de élite., Peer Reviewed, Postprint (author's final draft)

There is growing interest in defining the aberrant molecular differences between normal and tumor-associated fibroblasts (TAFs) that support tumor progression. For this purpose, we recently conducted a genome-wide DNA methylation profiling of TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer (NSCLC) patients, and reported a widespread hypomethylation concomitantly with focal gain of DNA methylation; in addition, we found evidence that a fraction of lung TAFs are fibrocytes in origin. Of note, the aberrant epigenome of lung TAFs had a global impact in gene expression and a selective impact on the TGF-ß pathway. To get insights on the functional implications of the latter impact, we analyzed the response of lung TAFs to exogenous TGF-ß1 in terms of activation and contractility. We found a larger expression of a panel of activation markers including a-SMA and collagen-I in TAFs compared to control fibroblasts. Likewise, TGF-ß1 elicited a larger contractility in TAFs than in CFs as assessed by traction force microscopy. These findings reveal that lung TAFs are hyperresponsive to TGF-ß1, which may underlie the expansion and/or maintenance of the tumor-promoting desmoplastic stroma in lung cancer., Postprint (author's final draft)

This study aims to assess the gene regulatory response from a group of 16 athletes and to observe the plasticity induced by their training regime on the gene expression response after their participation in an 82km race. Blood samples for differential gene expression (DGE) were collected before and after this effort from two groups of runners with different training regimes: elite and active. Analyses only focused on genes annotated as related to cardiac function (CF) and neural regulation (NR) from the KEGG PATHWAY Database. Thus, 13 pathways were considered accounting for a total of 629 genes. Training regime modulated the response to exercise based on a list of 18 ranked genes with significant DGE for elite runners while remained statistically insignificant for active athletes. UQCR11, COX7C and COX4I1 genes, related to mitochondrial respiratory chain, were down-regulated which may indicate mitochondrial function impairment in cardiac muscle. Increased expression levels were obtained for PIK3R2, PLCG2, IRAK3 genes from the positive signaling cascades of neurotrophins pathway, which may reveal an improved heart rate control thanks to a better cardiac sympathetic innervation., Postprint (author's final draft)