MYC驱动的人类和小鼠前列腺癌肿瘤微环境中的趋同改变。

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer.

作者信息

Graham Mindy K, Wang Rulin, Chikarmane Roshan, Wodu Bulouere, Vaghasia Ajay, Gupta Anuj, Zheng Qizhi, Hicks Jessica, Sysa-Shah Polina, Pan Xin, Castagna Nicole, Liu Jianyong, Meyers Jennifer, Skaist Alyza, Zhang Yan, Schuebel Kornel, Simons Brian W, Bieberich Charles J, Nelson William G, Lupold Shawn E, DeWeese Theodore L, De Marzo Angelo M, Yegnasubramanian Srinivasan

出版信息

bioRxiv. 2023 Oct 17:2023.09.07.553268. doi: 10.1101/2023.09.07.553268.

Abstract

The tissue microenvironment in prostate cancer is profoundly altered. While such alterations have been implicated in driving prostate cancer initiation and progression to aggressive disease, how prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) and rigorous molecular pathology of the comparative biology between human prostate cancer and key time points in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues, with validation in a large external data set, revealed that cancer cell-intrinsic activation of MYC signaling was the top up-regulated pathway in human cancers, representing a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Likewise, numerous non-malignant cell states in the tumor microenvironment (TME), including non-cancerous epithelial, immune, and fibroblast cell compartments, were conserved across individuals, raising the possibility that these cell types may be a sequelae of the convergent MYC activation in the cancer cells. To test this hypothesis, we employed a GEMM of prostate epithelial cell-specific MYC activation in two mouse strains. Cell communication network and pathway analyses suggested that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogrammed the TME during carcinogenesis, leading to the emergence of cascading cell state alterations in neighboring epithelial, immune, and fibroblast cell types that paralleled key findings in human prostate cancer. Importantly, among these changes, the progression from a precursor-enriched to invasive-cancer-enriched state was accompanied by a cell-intrinsic switch from pro-immunogenic to immunosuppressive transcriptional programs with coinciding enrichment of immunosuppressive myeloid and Treg cells in the immune microenvironment. These findings implicate activation of MYC signaling in reshaping convergent aspects of the TME of prostate cancer as a common denominator across the otherwise well-documented molecular heterogeneity of human prostate cancer.

摘要

前列腺癌中的组织微环境发生了深刻改变。虽然这些改变被认为与前列腺癌的起始以及进展为侵袭性疾病有关,但前列腺癌细胞及其前体细胞如何介导这些变化尚不清楚,部分原因是无法对人体组织中的疾病演变进行纵向研究。为了克服这一限制,我们对人类前列腺癌与前列腺癌基因工程小鼠模型(GEMM)疾病演变关键时间点之间的比较生物学进行了广泛的单细胞RNA测序(scRNA-seq)和严格的分子病理学研究。我们对人体组织的研究在一个大型外部数据集中得到了验证,结果显示MYC信号通路的癌细胞内在激活是人类癌症中上调最明显的通路,代表了人类前列腺癌众所周知的分子和病理异质性中的一个共同特征。同样,肿瘤微环境(TME)中的许多非恶性细胞状态,包括非癌上皮、免疫和成纤维细胞区室,在个体间是保守的,这增加了这些细胞类型可能是癌细胞中MYC激活趋同的后遗症的可能性。为了验证这一假设,我们在两种小鼠品系中构建了前列腺上皮细胞特异性MYC激活的GEMM。细胞通讯网络和通路分析表明,表达MYC癌基因的肿瘤细胞在致癌过程中直接或间接地对TME进行了重编程,导致相邻上皮、免疫和成纤维细胞类型中出现级联细胞状态改变,这与人类前列腺癌的关键发现相似。重要的是,在这些变化中,从前体富集状态到侵袭性癌症富集状态的转变伴随着细胞内在的从促免疫原性转录程序到免疫抑制转录程序的转变,同时免疫微环境中免疫抑制性髓样细胞和调节性T细胞富集。这些发现表明,MYC信号通路的激活在重塑前列腺癌TME的趋同方面起着作用,这是人类前列腺癌在其他方面有充分记录的分子异质性中的一个共同特征。

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