Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions
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Published:2024-01-29
Issue:1
Volume:16
Page:
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ISSN:1756-994X
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Container-title:Genome Medicine
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language:en
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Short-container-title:Genome Med
Author:
Mei ShenglinORCID, Alchahin Adele M., Tsea Ioanna, Kfoury Youmna, Hirz Taghreed, Jeffries Nathan Elias, Zhao Ting, Xu Yanxin, Zhang Hanyu, Sarkar Hirak, Wu Shulin, Subtelny Alexander O., Johnsen John Inge, Zhang Yida, Salari Keyan, Wu Chin-Lee, Randolph Mark A., Scadden David T., Dahl Douglas M., Shin John, Kharchenko Peter V., Saylor Philip J., Sykes David B., Baryawno Ninib
Abstract
Abstract
Background
Despite therapeutic advances, once a cancer has metastasized to the bone, it represents a highly morbid and lethal disease. One third of patients with advanced clear cell renal cell carcinoma (ccRCC) present with bone metastasis at the time of diagnosis. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined, hindering progress towards identification of therapeutic targets.
Methods
We collected fresh patient samples and performed single-cell transcriptomic profiling of solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), and liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow from patients undergoing hip replacement surgery (Benign). In addition, we incorporated single-cell data from primary ccRCC tumors (ccRCC Primary) for comparative analysis.
Results
The bone marrow of metastatic patients is immune-suppressive, featuring increased, exhausted CD8 + cytotoxic T cells, T regulatory cells, and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival and also markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption.
Conclusions
These results provide a comprehensive analysis of the bone marrow niche in the setting of human metastatic cancer and highlight potential therapeutic targets for both cell populations and communication channels.
Funder
NHLBI Division of Intramural Research Vetenskapsrådet prostate cancer foundation
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
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