ICSA2022

**ICSA2022 Groningen has been scheduled**

29th of September to 1st of October 2022

More details soon!

Dynamic regulation of myofibroblast phenotype in cellular senescence

​

Irene López-Antona, Constanza Contreras-Jurado, Laura Luque-Martín, Antonio Carpintero-Leyva, Paula González-Méndez, Ignacio Palmero

​

Cellular senescence is an antiproliferative response with a critical role in the control of cellular balance in diverse physiological and pathological settings. Here, we set to study the impact of senescence on the regulation of cell plasticity, focusing on the regulation of the myofibroblastic phenotype in primary fibroblasts. Myofibroblasts are contractile, highly fibrogenic cells with key roles in wound healing and fibrosis. Using cellular models of fibroblast senescence, we find a consistent loss of myofibroblastic markers and functional features upon senescence implementation. This phenotype can be transmitted in a paracrine manner, most likely through soluble secreted factors. A dynamic transcriptomic analysis during paracrine senescence confirmed the non-cell-autonomous transmission of this phenotype. Moreover, gene expression data combined with pharmacological and genetic manipulations of the major SASP signaling pathways suggest that the changes in myofibroblast phenotype are mainly mediated by the Notch/TGF-β axis, involving a dynamic switch in the TGF-β pathway. Our results reveal a novel link between senescence and myofibroblastic differentiation with potential implications in the physiological and pathological functions of myofibroblasts.

TRPC3 shapes the ER-mitochondria Ca 2+ transfer characterizing tumour-promoting senescence

Valerio Farfariello, Dmitri V. Gordienko, Lina Mesilmany, Yasmine Touil, Emmanuelle Germain, Ingrid Fliniaux, Emilie Desruelles, Dimitra Gkika, Morad Roudbaraki, George Shapovalov, Lucile Noyer, Mathilde Lebas, Laurent Allart, Nathalie Zienthal-Gelus, Oksana Iamshanova, Franck Bonardi, Martin Figeac, William Laine, Jerome Kluza, Philippe Marchetti, Bruno Quesnel, Daniel Metzger, David Bernard, Jan B. Parys, Loïc Lemonnier & Natalia Prevarskaya

​

Cellular senescence is implicated in a great number of diseases including cancer. Although alterations in mitochondrial metabolism were reported as senescence drivers, the underlying mechanisms remain elusive. We report the mechanism altering mitochondrial function and OXPHOS in stress-induced senescent fibroblasts. We demonstrate that TRPC3 protein, acting as a controller of mitochondrial Ca2+ load via negative regulation of IP3 receptor-mediated Ca2+ release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca2+ oscillations and elevates mitochondrial Ca2+ load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca2+ load and promotes escape from OIS-induced senescence. Cellular senescence evoked by TRPC3 downregulation in stromal cells displays a proinflammatory and tumour-promoting secretome that encourages cancer epithelial cell proliferation and tumour growth in vivo. Altogether, our results unravel the mechanism contributing to pro-tumour behaviour of senescent cells.

To learn more about young ICSA (yICSA), click here!