Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.
Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.
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DOI：
10.1038/s41467-021-25529-z
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发表时间：
2021-09-13
影响因子：
16.6
通讯作者：
Laughney AM
中科院分区：
文献类型：
--
作者：
Bakhoum MF;Francis JH;Agustinus A;Earlie EM;Di Bona M;Abramson DH;Duran M;Masilionis I;Molina E;Shoushtari AN;Goldbaum MH;Mischel PS;Bakhoum SF;Laughney AM
染色体不稳定性（CIN）和表观遗传学改变与肿瘤进展和转移有关;但这两个癌症标志如何相关仍知之甚少。通过在单细胞水平上整合遗传、表观遗传和功能分析，我们发现葡萄膜黑色素瘤（UM）（成人中最常见的眼内原发性癌症）的进展是由肿瘤细胞亚群中多梳抑制复合物1（PRC 1）的缺失驱动的。这导致PRC 1靶基因的转录去抑制和有丝分裂染色体分离错误。随后的CIN导致易破裂微核的形成，使基因组双链DNA（dsDNA）暴露于胞质溶胶。这引起肿瘤细胞内在的炎症信号传导，由cGAS-STING途径的异常激活介导。PRC 1抑制促进核增大，诱导与显著更差的患者存活和临床结果相关的转录应答，并增强在CIN或STING的药理学抑制后被拯救的迁移。因此，PRC 1的失调可以通过诱导CIN促进肿瘤进展，并代表了早期治疗干预的机会。驱动葡萄膜黑色素瘤（UM）进展的分子基础尚不清楚。在这里，作者表明，Polycomb抑制复合物1的丢失触发了染色体不稳定性，这促进了UM中的炎症信号传导和迁移。
Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention. The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
21.3
作者：
Bakhoum, Samuel F.;Thompson, Sarah L.;Manning, Amity L.;Compton, Duane A.
通讯作者：
Compton, Duane A.
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
16.6
作者：
Cheutin T;Cavalli G
通讯作者：
Cavalli G