Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts DOI Creative Commons

De‐Zhen Guo,

Xin Zhang, S Zhang

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Aug. 2, 2024

Abstract Background Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The of hepatocellular carcinoma (HCC) cellular level is not clear. Methods Integration analysis single-cell RNA sequencing data spatial transcriptomics was performed. Multiple methods were applied to investigate subtype HCC cells. functional characteristics, translation factors, clinical implications microenvironment associations different subtypes cells analyzed. interaction fibroblasts Results We established landscape malignant by integrated 52 5 data. identified three cells, including ARG1 + metabolism (Metab-subtype), TOP2A proliferation phenotype (Prol-phenotype), S100A6 pro-metastatic (EMT-subtype). Enrichment found that harbored features, metabolism, proliferating, epithelial-mesenchymal transition. Trajectory revealed both Metab-subtype EMT-subtype originated from Prol-phenotype. Translation factor showed exclusive activation SMAD3 TGF-β signaling pathway. dominated an unfavorable prognosis deserted microenvironment. uncovered positive loop between mediated SPP1-CD44 CCN2/TGF-β-TGFBR1 pairs. Inhibiting CCN2 disrupted loop, mitigated transformation EMT-subtype, suppressed Conclusion By establishing we three-subtype classification HCC. Among them, play crucial role Targeting feedback promising anti-metastatic strategy.

Language: Английский

Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment DOI Creative Commons

Chenxi Ma,

Chengzhe Yang,

Ai Peng

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 13, 2023

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays crucial role in remodeling the tumor microenvironment (TME). Here, through integrated analysis of spatial and single-cell transcriptomics data across six common cancer types, we identified four distinct functional subgroups CAFs described their distribution characteristics. Additionally, RNA sequencing (scRNA-seq) from three additional types two newly generated scRNA-seq datasets rare namely epithelial-myoepithelial carcinoma (EMC) mucoepidermoid (MEC), expanded our understanding CAF heterogeneity. Cell-cell interaction conducted within context highlighted pivotal roles matrix (mCAFs) angiogenesis inflammatory (iCAFs) shaping immunosuppressive microenvironment. In patients with breast (BRCA) undergoing anti-PD-1 immunotherapy, iCAFs demonstrated heightened capacity facilitating proliferation, promoting epithelial-mesenchymal transition (EMT), contributing to establishment an Furthermore, scoring system based on showed significant correlation immune therapy response melanoma patients. Lastly, provided web interface ( https://chenxisd.shinyapps.io/pancaf/ ) for research community investigate pan-cancer.

Language: Английский

Citations

104
Advances in single-cell RNA sequencing and its applications in cancer research DOI Creative Commons
Dezhi Huang,

Naya Ma,

Xinlei Li

et al.

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Aug. 24, 2023

Abstract Cancers are a group of heterogeneous diseases characterized by the acquisition functional capabilities during transition from normal to neoplastic state. Powerful experimental and computational tools can be applied elucidate mechanisms occurrence, progression, metastasis, drug resistance; however, challenges remain. Bulk RNA sequencing techniques only reflect average gene expression in sample, making it difficult understand tumor heterogeneity microenvironment. The emergence development single-cell (scRNA-seq) technologies have provided opportunities subtle changes biology identifying distinct cell subpopulations, dissecting microenvironment, characterizing cellular genomic mutations. Recently, scRNA-seq technology has been increasingly used cancer studies explore which increased understanding tumorigenesis evolution. This review summarizes basic processes their increasing applications research clinical practice.

Language: Английский

Citations

86
Friend or foe? The elusive role of hepatic stellate cells in liver cancer DOI
Bruno Cogliati, Chittampalli Yashaswini, Shuang Wang

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(10), P. 647 - 661

Published: Aug. 7, 2023

Language: Английский

Citations

67
Prognostic signatures of sphingolipids: Understanding the immune landscape and predictive role in immunotherapy response and outcomes of hepatocellular carcinoma DOI Creative Commons
Xin Zhang, Jinke Zhuge, Jinhui Liu

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 17, 2023

Hepatocellular carcinoma (HCC) is a complex disease with poor outlook for patients in advanced stages. Immune cells play an important role the progression of HCC. The metabolism sphingolipids functions both tumor growth and immune infiltration. However, little research has focused on using sphingolipid factors to predict HCC prognosis. This study aimed identify key genes (SPGs) develop reliable prognostic model based these genes.The TCGA, GEO, ICGC datasets were grouped SPGs obtained from InnateDB portal. A gene signature was created by applying LASSO-Cox analysis evaluating it Cox regression. validity verified GEO datasets. microenvironment (TME) examined ESTIMATE CIBERSORT, potential therapeutic targets identified through machine learning. Single-cell sequencing used examine distribution within TME. Cell viability migration tested confirm SPGs.We 28 that have impact survival. Using clinicopathological features 6 genes, we developed nomogram high- low-risk groups found distinct characteristics response drugs. Unlike CD8 T cells, M0 M2 macrophages be highly infiltrated TME high-risk subgroup. High levels good indicator immunotherapy. In cell function experiments, SMPD2 CSTA enhance survival Huh7 while silencing increased sensitivity lapatinib.The presents six-gene can aid clinicians choosing personalized treatments patients. Furthermore, uncovers connection between sphingolipid-related microenvironment, offering novel approach By focusing crucial like CSTA, efficacy anti-tumor therapy cells.

Language: Английский

Citations

49
Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives DOI Creative Commons

Ke-Yu Shen,

Ying Zhu,

Sun‐Zhe Xie

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: April 29, 2024

Abstract Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs been trend this area. Recently, dual blockade durvalumab plus tremelimumab has also emerged an effective for advanced However, majority HCC patients obtain benefits. Understanding immunological rationale exploring novel ways to improve efficacy immunotherapy drawn much attention. review, we summarize latest area, ongoing clinical trials immune-based therapies, well strategies chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, bispecific antibodies.

Language: Английский

Citations

49
PGAM1 Inhibition Promotes HCC Ferroptosis and Synergizes with Anti‐PD‐1 Immunotherapy DOI Creative Commons

Yi-Min Zheng,

Yining Wang, Lu Zhou

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(29)

Published: Sept. 14, 2023

Abstract The combination of immunotherapy and molecular targeted therapy exhibits promising therapeutic efficacy in hepatocellular carcinoma (HCC), but the underlying mechanism is still unclear. Here, phosphoglycerate mutase 1 (PGAM1) identified as a novel immunometabolic target by using bioinformatic algorithm based on multiple HCC datasets. PGAM1 highly expressed associated with poor prognosis response to immunotherapy. In vitro vivo experiments indicate that targeting inhibited cell growth promoted infiltration CD8 + T‐cells due decreased enzymatic activity. Mechanistically, inhibition promotes ferroptosis downregulating Lipocalin (LCN2) inducing energy stress ROS‐dependent AKT inhibition, which can also downregulate Programmed death 1‐ligand (PD‐L1). Moreover, an allosteric inhibitor (KH3) good antitumor effects patient‐derived xenograft (PDX) models enhanced anti‐PD‐1 subcutaneous orthotopic models. Taken together, findings demonstrate exerts effect promoting T‐cell synergize HCC. Targeting be new strategy “killing two birds one stone” for treatment.

Language: Английский

Citations

44
Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma DOI Creative Commons

Yau-Tuen Chan,

Cheng Zhang, Junyu Wu

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Sept. 6, 2024

Language: Английский

Citations

42
Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy DOI
Ziyi Li,

Rhea Pai,

Saurabh Gupta

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(1), P. 167 - 186

Published: Jan. 2, 2024

Language: Английский

Citations

41
Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer DOI
Fuming Li, Pingyu Liu, Mi Wen

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(1), P. 131 - 146

Published: Jan. 2, 2024

Language: Английский

Citations

32
Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response DOI Creative Commons
Alexander Coulton, Jun Murai, Danwen Qian

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 6, 2024

Abstract The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses broad spectrum of phenotypic diversity, due differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas tumour-associated macrophages (TAMs) fully captures this complexity. In addition, increased understanding diversity could help explain variable responses cancer patients immunotherapy. Our includes well established subsets as number additional ones. associate composition with tumour phenotype and show can vary between primary metastatic tumours growing sites like liver. also examine macrophage-T functional cross talk identify two TAMs associated T activation. Analysis TAM signatures large cohort immune checkpoint inhibitor-treated (CPI1000 + ) multiple response, including presence subset upregulate collagen-related genes. Finally, we demonstrate utility our data resource reference mapping novel datasets using projection. Overall, these advances represent important step both classification overcoming resistance immunotherapies cancer.

Language: Английский

Citations

28