Myeloid-like tumor hybrid cells in bone marrow promote progression of prostate cancer bone metastasis

Abstract

Background Bone metastasis is the leading cause of death in patients with prostate cancer (PCa) and currently has no effective treatment. Disseminated tumor cells in bone marrow often obtain new characteristics to cause therapy resistance and tumor recurrence. Thus, understanding the status of disseminated prostate cancer cells in bone marrow is crucial for developing a new treatment. Methods We analyzed the transcriptome of disseminated tumor cells from a single cell RNA-sequencing data of PCa bone metastases. We built a bone metastasis model through caudal artery injection of tumor cells, and sorted the tumor hybrid cells by flow cytometry. We performed multi-omics analysis, including transcriptomic, proteomic and phosphoproteomic analysis, to compare the difference between the tumor hybrid cells and parental cells. In vivo experiments were performed to analyze the tumor growth rate, metastatic and tumorigenic potential, drug and radiation sensitivity in hybrid cells. Single cell RNA-sequencing and CyTOF were performed to analyze the impact of hybrid cells on tumor microenvironment. Results Here, we identified a unique cluster of cancer cells in PCa bone metastases, which expressed myeloid cell markers and showed a significant change in pathways related to immune regulation and tumor progression. We found that cell fusion between disseminated tumor cells and bone marrow cells can be source of these myeloid-like tumor cells. Multi-omics showed the pathways related to cell adhesion and proliferation, such as focal adhesion, tight junction, DNA replication, and cell cycle, were most significantly changed in these hybrid cells. In vivo experiment showed hybrid cells had a significantly increased proliferative rate, and metastatic potential. Single cell RNA-sequencing and CyTOF showed tumor-associated neutrophils/monocytes/macrophages were highly enriched in hybrid cells-induced tumor microenvironment with a higher immunosuppressive capacity. Otherwise, the hybrid cells showed an enhanced EMT phenotype with higher tumorigenicity, and were resistant to docetaxel and ferroptosis, but sensitive to radiotherapy. Conclusion Taken together, our data demonstrate that spontaneous cell fusion in bone marrow can generate myeloid-like tumor hybrid cells that promote the progression of bone metastasis, and these unique population of disseminated tumor cells can provide a potential therapeutic target for PCa bone metastasis.

Analysis of uveal melanoma scRNA sequencing data identifies neoplastic-immune hybrid cells that exhibit metastatic potential

“…[32] Across all five patient samples, we determined that the identified hybrid clusters displayed far fewer inferred significant interactions with other cell types (Figure 4A), suggesting that hybrid cells may be less dependent on other cells to maintain their functional behavior and thus may be more prone to metastasis. [33] We also identified a conserved interaction between tyrosinase binding protein (TYROBP) present on hybrid cells and CD44 present on tumor cells, in all patients (Figure 4B and Supplemental File 4) [34,35]. Although little is known regarding TYROBP-CD44 signaling in cancer, TYROBP has been previously shown to be highly expressed in clear cell renal cell carcinoma CTCs.…”

Detection of neoplastic-immune hybrid cells with metastatic properties in uveal melanoma

“…5A), suggesting that hybrid cells may be less dependent on other cells to maintain their functional behavior and thus may be more prone to metastasis. (40) We also identi ed a conserved interaction between tyrosinase binding protein (TYROBP) present on hybrid cells and CD44 present on tumor cells, in all patients (Fig. 5B and Supplemental File 4) (41,42).…”

Novel Synergistic Probiotic Intervention: Transcriptomic and Metabolomic Analysis Reveals Ameliorative Effects on Immunity, Gut Barrier, and Metabolism of Mice during Salmonella typhimurium Infection

“…At this stage, the genes that exhibited notable differences in expression were analyzed for the enrichment of specific biological processes and pathways using GO terms and KEGG pathways. To explore GO and KEGG pathways, the R package (v4.2.2) [41] and KOBAS (3.0) [42] were used.…”