Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer.
Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer.
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DOI：
10.1038/s41467-021-23780-y
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发表时间：
2021-06-07
影响因子：
16.6
通讯作者：
Rickman DS
中科院分区：
文献类型：
--
作者：
Brady NJ;Bagadion AM;Singh R;Conteduca V;Van Emmenis L;Arceci E;Pakula H;Carelli R;Khani F;Bakht M;Sigouros M;Bareja R;Sboner A;Elemento O;Tagawa S;Nanus DM;Loda M;Beltran H;Robinson B;Rickman DS
尽管用于治疗晚期前列腺癌的高效雄激素受体(AR)导向疗法的发展取得了进展，但此类疗法的获得性耐药性经常接踵而至。很大一部分耐药疾病患者发展为AR阴性肿瘤，失去管腔特征并表现出神经内分泌特征(神经内分泌前列腺癌(NEPC))。AR阳性腺癌向AR阴性NEPC转化过程中的细胞异质性和分子进化尚不清楚。利用一种新的基因工程小鼠模型，我们已经表征了Rb1缺失和MYCN(编码N-Myc)过表达之间的协同作用，这导致了AR阴性、低分化且具有高转移潜力的肿瘤的形成。基于单细胞的方法揭示了转录组和染色质可及性的显著时间变化，这表明在向NEPC的过渡过程中出现了不同的细胞群体，以Ascl1和Pou2f3的差异表达为标志。此外，全球DNA甲基化和N-Myc环路在Rb1丢失后被重定向。总之，我们的数据为前列腺癌向NEPC的进展提供了洞察力。从AR阳性的腺癌到AR阴性的神经内分泌前列腺癌(NEPC)的肿瘤演变的异质性还没有完全的特征。在这里，作者建立了一个小鼠模型，以表明Rb1缺失和MYCN过度表达加速了向AR阴性的NEPC的进展，并鉴定了不同的NEPC细胞亚群的出现。
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC. The heterogeneity of tumor evolution from AR-positive, adenocarcinoma to AR-negative, neuroendocrine prostate cancer (NEPC) is not fully characterized. Here the authors generate a mouse model to show that Rb1 loss and MYCN overexpression accelerates the progression to AR-negative NEPC and identify emergence of distinct subpopulations of NEPC cells.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
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
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
48
作者：
Engstrom, Par G.;Steijger, Tamara;Sipos, Botond;Grant, Gregory R.;Kahles, Andre;Raetsch, Gunnar;Goldman, Nick;Hubbard, Tim J.;Harrow, Jennifer;Guigo, Roderic;Bertone, Paul
通讯作者：
Bertone, Paul