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

• Published in: Nature communications Vol. 15; no. 1; pp. 7414 - 20
• Main Authors: Graham, Mindy K., Wang, Rulin, Chikarmane, Roshan, Abel, Bulouere, Vaghasia, Ajay, Gupta, Anuj, Zheng, Qizhi, Hicks, Jessica, Sysa-Shah, Polina, Pan, Xin, Castagna, Nicole, Liu, Jianyong, Meyers, Jennifer, Skaist, Alyza, Zhang, Yan, Rubenstein, Michael, Schuebel, Kornel, Simons, Brian W., Bieberich, Charles J., Nelson, William G., Lupold, Shawn E., DeWeese, Theodore L., De Marzo, Angelo M., Yegnasubramanian, Srinivasan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/63; 38/1; 38/71; 38/91; 45; 631/67/327; 631/67/589/466; 64/110; 64/60; 692/4028/67/2329; Animals; Biological evolution; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinogens; Cell activation; Cell Communication; Cell interactions; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene sequencing; Genetic engineering; Heterogeneity; Human tissues; Humanities and Social Sciences; Humans; Male; Mice; Mice, Transgenic; multidisciplinary; Myc protein; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA-Seq; Science; Science (multidisciplinary); Signal Transduction; Single-Cell Analysis; Tumor microenvironment; Tumor Microenvironment - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51450-2

How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer. Alterations in the tumour microenvironment (TME) can contribute to prostate cancer progression, but it is unclear how tumours mediate those changes. Here, analysis of human prostate cancer tissues and key stages of prostate cancer progression in a genetically engineered mouse model using single-cell RNA-sequencing reveals the central role of MYC signalling in reprogramming the TME.