It is identified that lymph node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors.
Abstract
Neuroblastoma, a pediatric cancer derived from sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes. Primary neuroblastomas are well-characterized, but the mechanisms underlying metastasis remain poorly understood. Here, by using single-cell and spatial multiomics, we identified that lymph node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors. In addition, compared to primary adrenal masses, the metastatic niche display increased immunosuppressive myeloid programs, heightened immune checkpoint signaling, and lymphocyte exhaustion, which are indicative of immune evasion and dysfunction. Notably, metastatic neuroblastomas show elevated eIF4F translation machinery and XPO1 levels. Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multiomics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas.
This study comprehensively maps the coevolution of malignant thyrocyte plasticity and the immunosuppressive metastatic niche in thyroid cancer and provides a robust molecular rationale for developing next-generation immunotherapeutic strategies tailored to thyroid cancer.
Shu-hang Xu, Yaorong Su, Senmin Zhang et al.· Oncoimmunology· 0 citations
Intrahepatic metastasis in multifocal hepatocellular carcinoma is associated with poor prognosis and therapeutic resistance, yet the immune mechanisms driving disease progression remain unclear. Here, we analyzed genetic and immune differences between primary tumors and intrahepatic metastatic lesions using sequencing approaches and spatial validation methods. We found that metastatic lesions shared key genomic features with primary tumors but exhibited a distinct immunosuppressive environment enriched in myeloid and T cell populations. In particular, a subset of macrophages expressing glycoprotein nonmetastatic melanoma protein B (GPNMB) was consistently enriched in metastatic niches across multiple independent cohorts. These macrophages were spatially colocalized with CD8+ T cells exhibiting features of terminal exhaustion. Mechanistically, integrated multiomics and functional analyses revealed that GPNMB overexpression triggers lipid metabolic rewiring via the phosphatidylinositol 3-kinase/AKT-cyclooxygenase-2 cascade, leading to elevated prostaglandin E2 secretion, which directly suppresses CD8+ T cell cytotoxicity. Specific silencing of this subset using a dual-targeted, lipid-polymer nanoparticle (APLsiGpnmb) effectively reversed T cell exhaustion, inhibited metastasis, and synergized with anti-programmed death 1 immunotherapy in mouse models without inducing systemic toxicity. These findings identify GPNMB-positive macrophages as key metabolic and immune regulatory hubs, suggesting that targeting the GPNMB–prostaglandin E2 axis provides a promising precision therapeutic strategy for intrahepatic metastasis in multifocal hepatocellular carcinoma.
Yuyan Xu, Cheng Zhang, Zhuo-Cheng Ji et al.· Research· 0 citations
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies and has an extremely poor prognosis. Its progression is largely driven by a highly complex and immunosuppressive tumor microenvironment (TME), highlighting the urgent need for a deeper understanding of its molecular mechanisms. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided unprecedented opportunities to dissect cellular heterogeneity, spatial organization, and gene expression dynamics within the TME. In this review, we summarize the major scRNA-seq and ST technologies and their unique strengths in cancer research and highlight their integrated applications in revealing PDAC heterogeneity, stromal–immune interactions, and mechanisms of therapeutic resistance. We further discuss how these approaches can inform biomarker discovery and guide the development of novel therapeutic strategies. Together, these findings suggest that integrated single-cell and spatial transcriptomics offers transformative potential to advance precision oncology and improve outcomes for patients with pancreatic cancer.
Mengting Luo, Feng Shen, Wanli Xu et al.· Cancer Biology & Therapy· 0 citations
These results highlight novel prognostic markers and therapeutic vulnerabilities with translational potential for treating TNBC lung metastasis and establish Exoc4, the Hif-2α-Cd36 vasculogenic mimicry axis, Cxcrl1/2-Cxcr2 signaling, and Sftpc as critical mediators of metastatic adaptation.
Hsiao-Chen Lee, C. Kuo, Fang-Ming Chen et al.· Cell Death and Disease· 0 citations
How single-cell and spatial omics are reshaping the understanding of metabolic reprogramming and tumor–immune ecosystems in NSCLC is discussed, and how these findings may inform biomarker discovery, patient stratification, resistance monitoring, and rational combination therapy are discussed.
Zhenzhen Lian, Xu-Jing Wu, Yangyang Zhou et al.· Frontiers in Immunology· 0 citations
An integrated analysis of EwS tumor samples reveals a dynamic tumor–CAF continuum that is uniquely preserved in primary tumors and establishes a framework for identifying clinically relevant tumor-associated surface TAs, providing a foundation for the rational development of next-generation immunotherapies and precision-targeted therapies for patients with EwS.
Mohamed A. Sharif, Abdul S. Khan, R. Brentjens et al.· bioRxiv· 0 citations