Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling
Menée in vitro et à l'aide de modèles murins de mélanome, cette étude met en évidence un mécanisme par lequel la dihydroxyphénylalanine endogène bloque la prolifération des mélanocytes et des cellules de mélanome en inhibant la signalisation du récepteur muscarinique de l'acétylcholine M1
Melanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity and susceptibility to malignant transformation, independent of melanin and ultraviolet exposure. These differences result from dihydroxyphenylalanine (DOPA), a melanin precursor synthesized at higher levels in melanocytes from darkly pigmented skin. We used both high-throughput pharmacologic and genetic in vivo CRISPR screens to determine that DOPA limits melanocyte and melanoma cell proliferation by inhibiting the muscarinic acetylcholine receptor M1 (CHRM1) signaling. Pharmacologic CHRM1 antagonism in melanoma leads to depletion of c-Myc and FOXM1, both of which are proliferation drivers associated with aggressive melanoma. In preclinical mouse melanoma models, pharmacologic inhibition of CHRM1 or FOXM1 inhibited tumor growth. CHRM1 and FOXM1 may be new therapeutic targets for melanoma. DOPA, a melanin synthesis intermediate, inhibits oncogenic CHRM1 signaling in melanoma.
Science Advances 2022