Journal
SCIENCE ADVANCES
Volume 8, Issue 35, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abn4007
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Funding
- NIH/NCI [F31 CA250316, R01 CA163566, R41CA228695, R56AR079409]
- Department of Defense [81XWH2110860]
- Penn Skin Biology and Diseases Resource-based Center [P30-AR069589]
- Breast Cancer Research Foundation [BCRF-083, BCRF-084]
- University of Pennsylvania Dermatology Training Grant [T32AR007465]
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Research reveals that differences in DOPA synthesis between dark and light melanocytes play a role in regulating melanocyte and melanoma cell proliferation. Inhibiting CHRM1 or FOXM1 could be a potential new therapeutic approach for melanoma.
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 M-1 (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.
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