Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling

Doepner, Miriam, Lee, Inyoung, Natale, Christopher A, Brathwaite, Roderick, Venkat, Swati, Kim, Sung Hoon, Wei, Yiliang, Vakoc, Christopher R, Capell, Brian C, Katzenellenbogen, John A, Katzenellenbogen, Benita S, Feigin, Michael E, Ridky, Todd W (September 2022) Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling. Science Advances, 8 (35). eabn4007. ISSN 2375-2548

PDF 2022-Vakoc-Endogenous-DOPA-inhibits-melanoma-through-suppression-of-CHRM1-signaling.pdf Available under License Creative Commons Attribution Non-commercial. Download (5MB)

Abstract

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell signaling organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > cancer types > melanomas organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	Wei, Yiliang Vakoc, Christopher R.
Communities:	CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Vakoc lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	2 September 2022
Date Deposited:	06 Sep 2022 21:38
Last Modified:	02 May 2024 13:53
PMCID:	PMC10848963
URI:	https://repository.cshl.edu/id/eprint/40706

Actions (login required)

Administrator's edit/view item