Dr Nicole ARRIGHI

Research team

Biology and pathologies of melanocytes: From skin pigmentation to melanoma

From energy metabolism in fibroadipogenic muscle progenitors to RNA metabolism in metastatic uveal melanoma cells

Abstract

My thesis work focused on the energy metabolism of Pseudomonas mendocina. This aerobic bacterium shows a fermentative metabolism with production of organic acids in microaerophilia, thanks to a redirection of energy metabolism.
Metabolic plasticity is an essential component of cellular adaptation. I was able to explore a different facet of this in the study of adipose progenitors of skeletal muscle. The muscle stem cell model enabled me to study the factors triggering the differentiation of fibroadipogenic progenitors (FAP). The primordial role of the primary cilium was demonstrated in the fibrogenic differentiation and maintenance of myofibroblasts obtained from human adipose progenitors. Small RNA-seq of fibroadipogenic (FAP) and myogenic progenitors (MP) confirmed that FAP and MP expressed different miRNA subgroups. FibromiR expression was higher in PAFs than MPs and overexpressed in the presence of TGF-β1. The molecular signature of the miRNA199a-214 cluster is associated with fibrosis status. Our study demonstrated that FibromiR miR-214-3p is a key activator of PAF fibrogenesis by modulating the FGF2/FGFR1/TGF-β1 axis, opening new perspectives for the treatment of muscular dystrophy such as Duchenne muscular dystrophy.
Since 2020, I have joined the Melanocyte Biology and Pathology laboratory (C3M, Nice). My research project involves identifying exploitable vulnerabilities in uveal melanoma (UM) and developing a model for assessing the metastatic potential of melanocyte lineages. Initial results showed, by kinome screening, that inhibition of the KEOPS protein complex led to a slowdown in MU cell proliferation. This KEOPS complex is responsible for transcriptional modifications, in particular the modification of transfer RNA at adenine position 37 (t6A). The KEOPS complex is essential for protein biosynthesis. One of its subunits could represent an exploitable vulnerability in metastatic MU and open the way to new therapeutic avenues.

Keywords 

energy metabolism, fibroadipocyte progenitors, metastatic uveal melanoma, transfer RNA modification, t6A.