A single‐cell RNA sequencing atlas of 95 BoMs, 22 healthy bone marrows and 129 primary tumors spanning 10 cancer types, comprising 895,475 high‐quality transcriptomes, is presented to map cellular remodeling during bone metastatic colonization.
Abstract
Bone metastases (BoMs) are a major clinical challenge across cancer types, yet mechanistic insights remain limited by small cohorts and insufficient profiling depth. Here, we present a single‐cell RNA sequencing atlas of 95 BoMs, 22 healthy bone marrows (hBMs) and 129 primary tumors (PTs) spanning 10 cancer types, comprising 895,475 high‐quality transcriptomes, to map cellular remodeling during bone metastatic colonization. Malignant cells in BoMs converged on chromosomal instability—high proliferative states with enhanced angiogenic programs and suppressed immune‐inflammatory and metabolic pathways. The BoM immune landscape featured reduced cytotoxic lymphoid populations and expanded exhausted T‐cell states, with pronounced cancer type‐specific heterogeneity. BoM‐resident myeloid cells showed marked suppression of antigen presentation and phagocytosis, indicating immunosuppressive reprogramming. Stromal remodeling was characterized by enrichment of immunosuppressive CAFs, depletion of antigen‐presenting fibroblasts, reduced mesenchymal MHC expression, and expanded angiogenic endothelial programs. Cell–cell communication analyses predicted strengthened CXCL12–CXCR4 stromal–immune signaling. In vitro, the CXCL12–CXCR4 axis recruited CD8
+
T cells and enhanced their adhesion, spatially sequestering them from the tumor parenchyma, while CXCR4 blockade or CXCL12 knockdown significantly reduced tumor‐cell migration and invasion in vitro. This atlas defines convergent hallmarks of bone metastasis and highlights shared stromal–immune dependencies as therapeutic vulnerabilities.
Bone metastasis can remodel the bone marrow microenvironment, yet how metastatic tumors reshape hematopoiesis and immunity across marrow regions remains poorly defined. Here, we profile a cross-cancer single-cell atlas with 126,986 cells by integrating bone marrow samples (tumor, involved, and distal sites) from liver, prostate, and kidney cancer bone metastases, as well as benign controls, resolving 7 major lineages and 66 subpopulations. We identified coordinated immune suppression and niche remodeling that innate cells rose in peri-tumoral marrow but dropped in tumor sites, while adaptive T/B cells progressively depleted and stromal/epithelial compartments expanded. We further revealed a shift in myelopoiesis toward immunosuppressive monocyte/macrophage states with GMP-level lineage bias, alongside impaired erythropoiesis and B lymphopoiesis driven by myeloid-like reprogramming of precursors. Tumor sites were enriched with exhausted/stressed T cells, linked to inhibitory progenitor-T cell interactions (e.g., LGALS9-HAVCR2 and CLEC2-KLRB1). Non-hematopoietic support signals (CXCL12-CXCR4, ICAM1-SPN) were attenuated, and tumor programs included a marrow-specific metaprogram with IGFBP3/NAMPT signaling predicted to further destabilize the HSC niche. Overall, our study offers an integrated framework for decoding the metastatic marrow ecosystem by jointly targeting hematopoietic distortion, stromal collapse, and immune dysfunction.
Esophageal squamous cell carcinoma (ESCC) features epithelial heterogeneity and an immunosuppressive microenvironment, yet clinically relevant malignant epithelial states remain poorly defined. We integrated four single‐cell RNA‐sequencing datasets and 10 bulk transcriptomic cohorts totaling 1318 samples, and applied cross‐cohort differential expression, survival analysis, and a machine‐learning framework of 113 algorithm combinations to screen for malignant epithelial cell‐associated biomarkers. GNGT1 was prioritized for its consistent upregulation, prognostic association, and limited prior characterization in ESCC. Across independent cohorts, GNGT1 exhibited favorable diagnostic performance, while high expression correlated with poorer overall survival and more advanced local tumor status. Immune deconvolution consistently linked GNGT1‐high tumors to reduced CD8+ T‐cell infiltration, lower immune scores, and decreased cytotoxic T‐cell markers. Single‐cell analyses further associated GNGT1‐high epithelial cells with altered epithelial–immune communication involving MIF, prostaglandin, and CXCL signaling, alongside enrichment of epithelial–mesenchymal transition, mTORC1, and proliferative programs; qPCR confirmed elevated GNGT1 expression in ESCC cell lines. This study defines GNGT1 as a marker of an immunosuppressive malignant epithelial state, thereby bridging epithelial heterogeneity with immune remodeling in ESCC. These findings support GNGT1 as a candidate diagnostic, prognostic, and biologically informative biomarker warranting mechanistic and clinical validation.
Qian Yuan, Cheng Wang, Yin Chang et al.· Chemical Biology and Drug De...· 0 citations
Bone metastases showed marked suppression of tumor-intrinsic type I interferon (IFN-I) signaling and loss of antigen presentation, features that were strongly associated with reduced bone metastasis-free survival and could inform precision therapeutic strategies for PCa.
Katie L. Owen, L. Gearing, B. Niranjan et al.· Cancer Research· 0 citations
ABSTRACT Thymic epithelial tumors (TETs) are rare and heterogeneous malignancies whose aggressive epithelial states and microenvironmental organization remain poorly defined. Here, we integrated single‐cell RNA sequencing, spatial transcriptomics, multiplex immunofluorescence, bulk transcriptomics, functional assays, xenograft validation, and computational pathology to characterize malignant epithelial heterogeneity in TETs. We identified a CDH3‐associated malignant epithelial state located at the origin of malignant‐state trajectories and enriched for stem‐like and EMT‐related features. Spatial transcriptomics and multiplex immunofluorescence showed that CDH3+ tumor cells preferentially localized within an M2 macrophage‐rich immunosuppressive niche, while cell–cell communication analyses nominated CCN2–LRP1 as a candidate epithelial–myeloid crosstalk axis. A 68‐gene CDH3‐associated signature stratified TCGA‐THYM into biologically distinct subgroups with differences in survival, histology, genomic instability, and immune contexture. Patient‐derived thymic carcinoma organoids showed elevated CDH3 expression, and CDH3 silencing suppressed thymic carcinoma cell proliferation, migration, invasion, EMT/PI3K–Akt‐related signaling, and macrophage‐associated crosstalk. Candidate inhibitors showed antitumor activity in xenograft models. We also established a deep learning pathology model that captured CDH3‐associated morphology from routine H&E slides and predicted patient outcome. Together, these findings define CDH3 as a biomarker and therapeutic target linking malignant epithelial plasticity to immunosuppressive niche formation and adverse clinical behavior in TETs.
Yuntao Feng, Jing-Yu Chen, Lang Xia et al.· Advancement of science· 0 citations
These findings identify a tumor-adapted MC state that orchestrates immune evasion and tissue remodeling during CRC progression, supporting the notion that MC are reprogrammed toward an immune-suppressive and pro-tumorigenic phenotype.
E. Putro, Alessia Carnevale, Caterina Marangio et al.· Cell Death & Disease· 0 citations
Colorectal cancer liver metastasis (CRLM) develops within a liver-specific immune and stromal microenvironment, yet the natural killer (NK)-cell adaptations associated with this metastatic niche remain incompletely defined.
We integrated human single-cell RNA sequencing, an exploratory murine cross-species comparison, spatial transcriptomics, bulk transcriptomic cohorts, donor-level pseudobulk analyses, cell-cell communication, pseudotime and in silico perturbation analyses, together with multiplex immunofluorescence, conditioned-medium assays, ELISA and immunoblotting.
Across 73,486 cells from six anatomical sites, NK cells showed lower relative representation within the recovered T/NK compartment in primary tumors and liver metastases, while the residual compartment showed inflammatory remodeling. NK-cell reclustering identified CD56-associated and CD16-associated CCL4 source clusters that were analyzed jointly as a CCL4-enriched NK-cell transcriptional state characterized by NF-κB, TNF, MAPK and JAK-STAT programs. In paired GSE164522 samples from 10 patients, this state was independently recovered, with nominally higher CCL4-associated signal in liver metastases than in primary tumors that did not remain significant after Benjamini-Hochberg correction. Spatial and communication analyses associated the state with SPP1-positive macrophage and stromal programs without establishing causality. Tissue imaging, conditioned-medium assays, ELISA and immunoblotting provided complementary marker-level and model-system support for CCL4-associated inflammatory activity and NF-κB pathway responsiveness.
CRLM is associated with altered NK-cell representation among recovered cells and a reproducible CCL4-enriched inflammatory NK-cell transcriptional state. Its association with inflammatory and myeloid-stromal programs across independent, spatial and model-system analyses provides a focused framework for future lineage-restricted and
in vivo
studies.
Li-Hong Lin, Michael Xu, Xiao-Chun Gu et al.· Frontiers in Immunology· 0 citations
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