Snail1 factor behaves as a therapeutic target in renal fibrosis.

Kidney fibrosis is a devastating disease that leads to organ failure, and no specific treatment is available to preserve organ function. In fibrosis, myofibroblasts accumulate in the interstitium leading to massive deposition of extracellular matrix and organ disfunction. The origin of myofibroblasts is multiple and the contribution of renal epithelial cells after undergoing epithelial-to-mesenchymal transition (EMT) is still debated. In a model unable to reactivate the EMT inducer Snail1 upon damage, we show that Snail1 is required in renal epithelial cells for the development of fibrosis. Damage-mediated Snail1 reactivation induces a partial EMT that relays fibrotic and inflammatory signals to the interstitium through the activation of TGF-β and NF-B pathways. Snail1-induced fibrosis can be reverted in vivo and inhibiting Snail1 in a model of obstructive nephropathy highly ameliorates fibrosis. These results reconcile conflicting data on the role of EMT in renal fibrosis and provide avenues for the design of antifibrotic therapies.pre-print8435 K

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Reguladores de la progresión de melanoma

Trabajo presentado al 8º Webinar SEBBM: Elevator Pitch, celebrado el 24 de septiembre de 2021.Peer reviewe

Determinantes del tráfico intracelular del receptor de melanocortinas humano 1 : alteraciones en variantes alélicas asociadas a melanoma / Berta López Sánchez-Laorden; directores, Celia Jiménez-Cervantes Frigols, José Carlos García -Borrón Martínez.

Tesis-Universidad de Murcia.Consulte la tesis en: BCA. GENERAL. ARCHIVO UNIVERSITARIO. T.M. 3624

Phenotypic plasticity in melanoma

Trabajo presentado al 10th Curie Institute Paris Sud University InternationalGraduate Course on Development and Cancer: a Virtual Edition, celebrada del 1 al 4 de diciembre de 2020.Peer reviewe

Phenotypic plasticity in melanoma

Trabajo presentado al 11th Curie Institute Paris Sacaly University International Graduate Course on Development and Cancer, celebrado del 30 de noviembre al 3 de diciembre de 2021.Peer reviewe

Melanoma y metástasis cerebral, claves para su prevención

Trabajo presentado a la XIII Semana de la Ciencia del Centro Cultural Virgen del Carmen, celebrada en Torrevieja el 8 de noviembre de 2021.El cáncer de piel se desarrolla desde los melanocitos, células que protegen de las radiaciones ultravioleta. La radiación genera mutaciones en el ADN que derivan en cáncer. La investigadora está estudiando un receptor implicado en la síntesis de melanocitos. Después de detallar los tipos de cáncer de piel (cutáneo, ocular, acral y mucoso), Berta López pasó a hablar de los factores de riesgo, que pueden ser genéticos o medioambientales. Sobre tal aspecto, destacó el hecho de que la población del norte de Europa padece en mayor medida este cáncer por tener en general una piel más clara, no porque reciban mayores horas de sol. La enfermedad se agrava cuando las células cancerosas profundizan y llegan a los vasos sanguíneos o linfáticos, hasta el extremo de dificultar la supervivencia del paciente. De ahí la importancia de la prevención y del diagnóstico precoz. La ponente advirtió de que las cremas protegen sólo parcialmente de los efectos del sol, por lo que son necesarias medidas adicionales, por ejemplo, evitar los bronceados con rayos ultravioleta o determinados esmaltes en las uñas (que provocarían el melanoma acral). La metástasis cerebral es un campo en el que aún queda mucho por avanzar. Actualmente se está investigando el efecto de los rayos ultravioleta en las microglías, los macrófagos del cerebro (células del sistema inmune innato del cerebro, primera línea de defensa contra organismos extraños).Peer reviewe

Antifibrotic drugs as therapeutic tools in resistant melanoma

News & Views.Melanoma is the most aggressive form of skin cancer. Together with the recent advances in immunotherapy, targeted therapy with inhibitors of the Mitogen Activated Protein Kinase (MAPKi) pathway including BRAF and MEK inhibitors has greatly improved the clinical outcome of these patients. Unfortunately, due to genetic and non-genetic events, many patients develop resistance to MAPKi. Melanoma phenotypic plasticity, understood as the ability of melanoma cells to dynamically transition between different states with varying levels of differentiation/dedifferentiation, is key for melanoma progression. Lineage plasticity has also emerged as an important mechanism of non-genetic adaptive melanoma drug resistance in the clinic (Arozarena & Wellbrock, 2019), highlighting the need for a deeper characterization of the mechanisms that control this process. In this issue of EMBO Molecular Medicine, Diazzi et al (2022) identify a mechanism regulating MAPKi-induced phenotypic plasticity and resistance, providing evidence to support the use of an anti-fibrotic drug as a potential novel combinatorial therapeutic approach.Peer reviewe

Microenvironmental regulation of melanoma progression, role of Snail1

Resumen del póster presentado al European Developmental Biology Congress (EDBC), celebrado en Alicante del 23 al 26 de octubre de 2019.Melanoma is the most deadly form of skin cancer due to its high metastatic abilities and resistance to treatments. Hyperactivation of the MAPK pathway is responsible for 90% of melanomas with mutations in BRAF and NRAS, accounting for 50% and 20% of the melanoma cases, respectively. In addition, the tumour microenvironment plays a key role in melanoma progression. Reactivation of embryonic programmes in cancer cells is associated to tumour progression and resistance to therapies. However, the role of the reactivation of such programmes in cells from the tumour microenvironment is not well characterized. Cancer-associated fibroblasts (CAFs), very abundantly present in the tumour surrounding stroma, are a population of activated fibroblasts whose activity associates with tumour progression and aggresiveness. CAFs produce extracellular matrix components, paracrine growth factors, cytokines and proteolytic enzymes, contributing to generate a desmoplastic response around cancer cells that is very similar to that at sites of wound or fibrosis. Snail1 is an EMT-TF (epithelial-to-mesenchymal transition transcription factor) expressed during development and reactivated in pathological situations including cancer and fibrosis. Snail1 is expressed in activated fibroblasts associated to damaged epithelial cells in renal fibrosis and increases evidences support its pro-tumorigenic role when expressed in CAFs from breast or colorrectal cancer. Our preliminary results show that Snail1 is expressed in cells from the melanoma microenvironment. We have established BRAF-driven murine melanoma cell lines and conditional mouse models to block Snail1 expression in cells from the tumour microenvironment and assess the impact on melanoma progression.Peer reviewe

Contribution of Snail1 in the tumour microenvironment to the regulation of melanoma progression: A target for therapeutic intervention

Resumen del póster presentado a la VIB Conferences Series: Tumor Heterogeneity, Plasticity and Therapy, celebrado virtualmente del 5 al 6 de mayo de 2021.Melanoma is a very malignant form of skin cancer due to its high metastatic abilities and resistance to therapies. MAPK pathway is hyperactivated in 90% of melanomas with mutations in BRAF responsible for approximately 50% of the cases. Tumour cells reside in a highly heterogeneous tumour microenvironment (fME), composed by local and recru ited cells including immune infiltrate cells, fibroblasts and blood vessels composed by endothelial cells and pericytes. lt has become clear that the crosstalk between tumour and stromal cells plays a key role in cancer progression. Activated fibroblasts, known as Cancer -associated fibroblasts (CAFs), are the main stromal cells within the reactive stroma and possess many pro-tumorigenic properties via secretion of growth factors, cytokines, chemokines and the degradation of extracellular matrix. 5nail1 is an epithelialto-mesenchymal transition transcription factor expressed during development and reactivated in pathological situations including cancer and fibrosis. Snail1 is expressed in activated fibroblasts associated to damaged epithelial cells in renal fibrosis and increasing evidence supports its pro-tumorigenic role when expressed in CAFs from breast or colorectal cancer. We have established BRAF-driven murine melanoma cell lines and conditional mouse models to deplete Snail1 expression in TME cells and assessed its impact on melanoma progression. Our results showthatSnail1 is highly expressed in cells from TME, predominantly in CAFs. Snail1-silencing in TME decreases tumour sizes and metastatic tumour burden in lungs. The investigation of a combination therapy cotargeting tumour cells and CAFs may provide a promising new strategy to improve patient's prognosis.Peer reviewe