CHRM1 是一种可药物治疗的黑色素瘤靶标，其内源性活性由 DOPA 生产中的遗传变异决定,bioRxiv - Cancer Biology

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CHRM1 是一种可药物治疗的黑色素瘤靶标，其内源性活性由 DOPA 生产中的遗传变异决定
bioRxiv - Cancer Biology Pub Date : 2021-07-15 , DOI: 10.1101/2021.03.03.433757
Miriam Doepner , Christopher A. Natale , Todd W. Ridky

与深色皮肤的人相比，浅色皮肤的人患黑色素瘤的风险高 30 倍。在这里，我们表明这种差异不仅仅是由黑色素及其紫外线辐射 (UVR) 屏蔽效果造成的。使用代表完整人类皮肤色素连续体的原代人类黑色素细胞和几个临床前黑色素瘤模型，我们表明暗黑色素细胞和亮黑色素细胞之间的细胞内在差异调节黑色素细胞增殖能力、整体细胞分化状态和恶性转化的易感性，独立于黑色素和紫外线接触。我们确定这些差异是由二羟基苯丙氨酸 (DOPA) 造成的，这是一种黑色素前体，在深色皮肤的黑色素细胞中合成的水平较高。尽管以前不知道 DOPA 具有特定的信号传导活性，我们使用高通量药理学和基因体内 CRISPR 筛选来确定多巴通过直接抑制毒蕈碱乙酰胆碱受体 M1 (CHRM1) 来限制黑素细胞和黑素瘤细胞增殖，这是一种以前未知的与多巴结合的 G 蛋白偶联受体 (GPCR)，也不影响黑色素瘤的病理生物学。黑色素瘤中的药理学 CHRM1 拮抗作用导致 c-Myc 和 FOXM1 耗尽，这两者都是与侵袭性黑色素瘤相关的增殖驱动因素。在使用免疫缺陷小鼠和同基因免疫活性小鼠的临床前小鼠黑色素瘤模型中，CHRM1 或 FOXM1 的药理学抑制抑制了肿瘤生长。CHRM1 和 FOXM1 可能是黑色素瘤的新治疗靶点。

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CHRM1 is a Druggable Melanoma Target Whose Endogenous Activity is Determined by Inherited Genetic Variation in DOPA Production

Melanoma risk is 30 times higher in people with lightly pigmented skin compared to those with darkly pigmented skin. Here we show that this difference results from more than melanin pigment and its ultraviolet radiation (UVR) shielding effect. Using primary human melanocytes representing the full human skin pigment continuum and several preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity, overall cellular differentiation state, and susceptibility to malignant transformation, independently of melanin and UV exposure. We determined that these differences result from dihydroxyphenylalanine (DOPA), a melanin precursor synthesized at higher levels in melanocytes from dark skin. Although DOPA was not previously known to have specific signaling activity, we used both high throughput pharmacologic and genetic in vivo CRISPR screens to determine that DOPA limits melanocyte and melanoma cell proliferation by directly inhibiting the muscarinic acetylcholine receptor M1 (CHRM1), a G Protein-Coupled Receptor (GPCR) not previously known to bind DOPA, nor to affect melanoma pathobiology. 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 using both immune deficient and syngeneic immune competent mice, pharmacologic inhibition of CHRM1 or FOXM1 inhibited tumor growth. CHRM1 and FOXM1 may be new therapeutic targets for melanoma.

更新日期：2021-07-16

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