This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.

Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor–ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging.Methods: We integrated laboratory data and public cohorts to conduct a multi-omics analysis of HCC, which included bulk RNA sequencing, proteomic analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics sequencing (ST-seq), and genome sequencing. We constructed a tumor purity (TP) and tumor microenvironment (TME) prognostic risk model. Proteomic analysis validated the TP-TME-related signatures. Joint analysis of scRNA-seq and ST-seq revealed characteristic clusters associated with TP high-risk subtypes, and immunohistochemistry confirmed the expression of key genes. We conducted functional enrichment analysis, transcription factor activity inference, cell-cell interaction, drug efficacy analysis, and mutation information analysis to identify a novel subtype of HCC.Results: Our analyses constructed a robust HCC prognostic risk prediction model. The patients with TP-TME high-risk subtypes predominantly exhibit hypoxia and activation of the Wnt/beta-catenin, Notch, and TGF-beta signaling pathways. Furthermore, we identified a novel subtype, XPO1+Epithelial. This subtype expresses signatures of the TP risk subtype and aligns with the biological behavior of high-risk patients. Additional analyses revealed that XPO1+Epithelial is influenced primarily by fibroblasts via ligand-receptor interactions, such as FN1-(ITGAV+ITGB1), and constitute a significant component of the TP-TME subtype. Moreover, XPO1+Epithelial interact with monocytes/macrophages, T/NK cells, and endothelial cells through ligand-receptor pairs, including MIF-(CD74+CXCR4), MIF-(CD74+CD44), and VEGFA-VEGFR1R2, respectively, thereby promoting the recruitment of immune-suppressive cells and angiogenesis. The ST-seq cohort treated with Tyrosine Kinase Inhibitors (TKIs) and Programmed Cell Death Protein 1 (PD-1) presented elevated levels of TP and TME risk subtype signature genes, as well as XPO1+Epithelial, T-cell, and endothelial cell infiltration in the treatment response group. Drug sensitivity analyses indicated that TP-TME high-risk subtypes, including sorafenib and pembrolizumab, were associated with sensitivity to multiple drugs. Further exploratory analyses revealed that CTLA4, PDCD1, and the cancer antigens MSLN, MUC1, EPCAM, and PROM1 presented significantly increase expression levels in the high-risk subtype group.Conclusions: This study constructed a robust prognostic model for HCC and identified novel subgroups at the single-cell level, potentially assisting in the assessment of prognostic risk for HCC patients and facilitating personalized drug therapy.

Genomic instability facilitates the evolution of cells, tissues, organs, and species. The progression of human malignancies can be regarded as the accumulation of genomic instability, which confers a high evolutionary potential for tumor cells to adapt to continuous changes in the tumor microenvironment. Nasopharyngeal carcinoma (NPC) is a head-and-neck squamous-cell carcinoma closely associated with Epstein–Barr virus (EBV) infection. NPC progression is driven by a combination of accumulated genomic instability and persistent EBV infection. Here, we present a review of the key characteristics of genomic instability in NPC and the profound implications of EBV infection. We further discuss the significance of profiling genomic instability for the assessment of disease progression and treatment efficacy, as well as the opportunities and challenges of targeted therapies for NPC based on its unique genomic instability.

The pre-metastatic niche constructed by cancer-associated fibroblasts (CAFs) plays a key role in the hypoxic tumor microenvironment (TME), promoting hepatocellular carcinoma (HCC) metastasis. Integrin, which is involved in cell-to-cell or cell-to-matrix interactions and TME regulation, affects tumor metastasis. However, the complex interactions between integrin-mediated HCC cells and CAFs remain unclear. Co-culture experiments were used to assess the behaviors of HCC cells and CAFs, demonstrating HCC metastatic traits and CAFs activation in vitro. Transcriptome sequencing analysis and molecular detection identified key genes, with overexpression and knockdown experiments further confirming their roles in HCC progression. Xenograft models validated these findings in vivo. We showed that HCC cells induced the conversion of normal hepatic stellate cells (HSCs) into CAFs and recruit additional CAFs, driven by lactate produced by HCC. Integrin beta 4 (ITGB4) was identified as a key gene in the process. Inhibiting ITGB4 reduced lactate secretion, reversed CAFs activation and recruitment, and decreased HCC metastasis, while overexpressing ITGB4 significantly enhanced these malignant phenotypes. ITGB4 influences glycolysis and HCC metastasis through the AKT/HK2 signaling pathway, and CAFs activation and recruitment through the TGF-β/Smads signaling pathway. Compared to tumors derived from control cells, ITGB4-knockdown tumors showed fewer and smaller intrahepatic metastatic nodules, reduced lactate production and CAFs formation, along with inhibition of AKT/HK2 and TGF-β/Smads signaling pathways. Our findings highlighted the impact of hypoxia on HCC progression, revealing the roles of ITGB4-mediated glycolysis and lactate-induced CAFs in the pre-metastatic niche on HCC metastasis.

Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.