Project description:Substantial heterogeneity in molecular features, patient prognoses, and therapeutic responses in head and neck squamous cell carcinomas (HNSCC) highlights the urgent need to develop molecular classifications that reliably and accurately reflect tumor behavior and inform personalized therapy. Here, we leveraged the similarity network fusion bioinformatics approach to jointly analyze multi-omics datasets spanning copy number variations, somatic mutations, DNA methylation, and transcriptomic profiling and derived a prognostic classification system for HNSCC. The integrative model consistently identified three subgroups (IMC1-3) with specific genomic features, biological characteristics, and clinical outcomes across multiple independent cohorts. The IMC1 subgroup included proliferative, immune-activated tumors and exhibited a more favorable prognosis. The IMC2 subtype harbored activated EGFR signaling and an inflamed tumor microenvironment with cancer-associated fibroblast/vascular infiltrations. Alternatively, the IMC3 group featured highly aberrant metabolic activities and impaired immune infiltration and recruiting. Pharmacogenomics analyses from in silico predictions and from patient-derived xenograft model data unveiled subtype-specific therapeutic vulnerabilities including sensitivity to cisplatin and immunotherapy in IMC1 and EGFR inhibitors (EGFRi) in IMC2, which was experimentally validated in patient-derived organoid models. Two signatures for prognosis and EGFRi sensitivity were developed via machine learning. Together, this integrative multi-omics clustering for HNSCC improves current understanding of tumor heterogeneity and facilitates patient stratification and therapeutic development tailored to molecular vulnerabilities.
Project description:Integrative multi-omics analyses identify molecular subtypes of head and neck squamous cell carcinoma with distinct therapeutic vulnerabilities
Project description:H3K27M diffuse intrinsic pontine gliomas (DIPG) exhibit cellular heterogeneity comprising less-differentiated, stem-like glioma cells that resemble oligodendrocyte precursors (OPC) and more differentiated astrocyte (AC)-like cells. H3K27M DIPG stem-like cells exhibit tumor-seeding capabilities in vivo, a feature lost or greatly diminished in the more differentiated AC-like cells. In this study, we established isogenic in vitro models of DIPG that closely recapitulated the OPC-like and AC-like phenotypes of DIPG cells. Using these tools, we performed transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs operative in the different cellular states. From this, we defined new strategies to selectively target metabolic vulnerabilities within the specific tumor populations. Namely, we showed that the AC-like cells exhibited a more mesenchymal phenotype and were thus sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulated cholesterol metabolism and mitochondrial oxidative phosphorylation (OXPHOS) and were accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors showed efficacy and extended survival in preclinical orthotopic models established with stem-like H3K27M DIPG cells. Together, this study demonstrates that cellular subtypes within DIPGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.
Project description:MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on-target leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell cycle arrest and apoptosis. We further show that an orally available small molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
Project description:MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on-target leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell cycle arrest and apoptosis. We further show that an orally available small molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.