单细胞与虚拟扰动解析HCC演进及治疗靶向
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TL;DR — A WeChat walkthrough of an NPJ Precision Oncology study that integrates large-scale single-cell and spatial transcriptomics across normal liver, primary HCC, portal vein tumor thrombus, and metastatic lymph nodes, then uses Geneformer-based in silico perturbation to nominate HSP90B1 as a convergent therapeutic target. It matters as a template for pairing atlas-scale profiling with foundation-model virtual knockouts to prioritize drug targets.
- cNMF on CopyKAT-called malignant cells yields four shared meta-programs — differentiated-metabolic (good prognosis), proliferative-stress, MYC-biosynthesis-immune, and EMT-inflammatory — that map onto Hoshida/Boyault subtypes and show state-specific drug vulnerabilities (HSP90/MEK, BCL-2, taxanes; HDAC inhibitors ineffective in the metabolic state).
- Progression is accompanied by immunosuppressive Macro-SPP1/Macro-TREM2 expansion; spatial deconvolution plus MISTy/PROGENy identifies a TGFβ-enriched niche of Endo-ESM1 endothelium with Fib-POSTN/Fib-CD36 fibroblasts adjacent to proliferative-stress and EMT-inflammatory tumor cells, with hypoxia elevated at the periphery.
- Geneformer virtual knockouts across three desired state transitions (Macro-SPP1→Macro-CXCL9, malignant→normal hepatocyte, Endo-ESM1→Endo-EDNRB) converge on 11 genes; DepMap CRISPR dependency plus TCGA-LIHC expression narrow these to EEF1A1, ACTB, and HSP90B1.
- HSP90B1 (GRP94) is favored: strong expression–dependency correlation (r = −0.874), diffuse overexpression in non-responders to both cabozantinib+nivolumab and sorafenib, and significant association with poor overall survival — unlike EEF1A1 (no OS link) or housekeeping ACTB.
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单细胞与虚拟扰动解析HCC演进及治疗靶向
TL;DR — A WeChat walkthrough of an NPJ Precision Oncology study that integrates large-scale single-cell and spatial transcriptomics across normal liver, primary HCC, portal vein tumor thrombus, and metastatic lymph nodes, then uses Geneformer-based in silico perturbation to nominate HSP90B1 as a convergent therapeutic target. It matters as a template for pairing atlas-scale profiling with foundation-model virtual knockouts to prioritize drug targets.
- cNMF on CopyKAT-called malignant cells yields four shared meta-programs — differentiated-metabolic (good prognosis), proliferative-stress, MYC-biosynthesis-immune, and EMT-inflammatory — that map onto Hoshida/Boyault subtypes and show state-specific drug vulnerabilities (HSP90/MEK, BCL-2, taxanes; HDAC inhibitors ineffective in the metabolic state).
- Progression is accompanied by immunosuppressive Macro-SPP1/Macro-TREM2 expansion; spatial deconvolution plus MISTy/PROGENy identifies a TGFβ-enriched niche of Endo-ESM1 endothelium with Fib-POSTN/Fib-CD36 fibroblasts adjacent to proliferative-stress and EMT-inflammatory tumor cells, with hypoxia elevated at the periphery.
- Geneformer virtual knockouts across three desired state transitions (Macro-SPP1→Macro-CXCL9, malignant→normal hepatocyte, Endo-ESM1→Endo-EDNRB) converge on 11 genes; DepMap CRISPR dependency plus TCGA-LIHC expression narrow these to EEF1A1, ACTB, and HSP90B1.
- HSP90B1 (GRP94) is favored: strong expression–dependency correlation (r = −0.874), diffuse overexpression in non-responders to both cabozantinib+nivolumab and sorafenib, and significant association with poor overall survival — unlike EEF1A1 (no OS link) or housekeeping ACTB.