{'fraction_non_alphanumeric': 0.022735884804850323, 'fraction_numerical': 0.007957559681697613, 'mean_word_length': 5.821705426356589, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Relative DOPA Deficiency in Lightly Pigmented Skin Contributes to UV-Independent Melanoma Susceptibility

Melanoma risk is higher for people with lightly pigmented skin (1:38) compared to those with darkly pigmented skin (1:1000). While this difference is typically attributed to the ultraviolet radiation (UVR) shielding effect of melanin pigment, here we show that other cell-intrinsic differences between dark and light MCs, independent of melanin and UV, regulate MC proliferative capacity, cellular differentiation state, and susceptibility to malignant transformation. These differences are driven by dihydroxyphenylalanine (DOPA), a melanin synthesis intermediate, and result from DOPA antagonism of the muscarinic acetylcholine receptor M1 (CHRM1), a G Protein-Coupled Receptor (GPCR) expressed in MCs, but not previously known to bind DOPA, nor to affect melanoma pathobiology. Pharmacologic CHRM1 antagonism in melanoma leads to downregulation of c-Myc and FOXM1, both of which are proliferation drivers associated with aggressive melanoma. In preclinical melanoma models, pharmacologic CHRM1 inhibition in vivo inhibited melanoma growth. CHRM1 may be a new therapeutic target for melanoma. Statement of Significance A previously unrecognized ability of dihydroxyphenylalanine (DOPA) to inhibit the muscarinic acetylcholine receptor M1 (CHRM1) in melanocytes contributes to decreased melanoma susceptibility in darkly pigmented skin, independent of ultraviolet exposure. Pharmacologic CHRM1 inhibition inhibits melanoma in preclinical melanoma models, indicating that CHRM1 may be a new therapeutic target for melanoma. Introduction Melanoma is the most lethal form of skin cancer and worldwide incidence is increasing. Despite advances in modern immune and targeted therapies, most patients with metastatic melanoma still die from their disease and new treatment approaches are needed.1,2 Clues to new therapeutic approaches may lie in understanding the mechanisms by which melanoma differentially affects different populations of people. Here we consider why the lifetime risk for cutaneous melanoma is substantially higher for people with lightly pigmented skin compared to those with darkly pigmented skin, even when they live in the same geographic region and are thereby exposed to similar amounts of UVR.3 Melanoma develops from melanocytes (MCs), which normally reside in the basal layer of skin and hair follicles where they produce melanin pigment, the primary determinant of skin and hair color. Melanogenesis is a complex, multi-step process that begins with the non-essential amino acid L-tyrosine and results in the