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Abstract Metastasis is the primary cause of death in patients with solid tumors, yet the treatment-refractory metastatic microenvironment is poorly characterized. To gain a comprehensive understanding of microenvironmental regulation of human metastasis, we performed single-cell RNA sequencing covering endothelial, stromal, myeloid, lymphoid, and malignant cells from 28 lung and liver samples of the metastatic microenvironment and metastasis-free adjacent microenvironment from patients with metastatic adrenocortical carcinoma compared to healthy donors for a total of 275, 903 cells. We discovered that the adjacent microenvironment in patients with metastatic cancer is significantly different from healthy tissue without cancer: The adjacent microenvironment has many immunosuppressive and pro-tumorigenic features similar to primary tumor and metastatic tissue. As adjacent tissues are potential sites for subsequent metastasis, the shared changes between the adjacent and metastatic microenvironments suggest that these elements of the treatment-refractory metastatic microenvironment may dictate metastasis. Importantly, these pathologic features of the adjacent and metastatic microenvironments associate with poor outcomes for patients and may be targetable. Lastly, we identify a mechanism by which tumor cells may be remotely driving and coordinating these changes in both the metastatic and adjacent microenvironments. Taken together, our study identifies shared and microenvironment-specific changes underlying a global program of metastasis. Citation Format: Etan R. Aber, Cristina F. Contreras, Mohd Omar Sikder, Kathy P. Li, Greta E. Forbes, Vishaka Gopalan, Sridhar Hannenhalli, Rosandra N. Kaplan. Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB308.
Aber et al. (Fri,) studied this question.