Project description:The inter-patient variability of tumor proteomes has been investigated on a large scale but many tumors display also intra-tumoral heterogeneity (ITH) regarding morphological and genetic features. To what extent the local proteome of tumors intrinsically differs remains largely unknown. Here, we used hepatocellular carcinoma (HCC) as a model system, to quantify both inter- and intra-tumor heterogeneity across human patient specimens with spatial resolution. We first defined proteomic features that robustly distinguish neoplastic from the directly adjacent non-neoplastic tissue by integrating proteomic data from human patient samples and genetically defined mouse models with available gene expression data. We then demonstrated the existence of intra-tumoral variations in protein abundance that re-occur across different patient samples, and affect clinically relevant proteins, even in the absence of obvious morphological differences or genetic alterations. Our work demonstrates the suitability and the benefits of using mass spectrometry based proteomics to analyze diagnostic tumor specimens with spatial resolution
Project description:Our study provides a comprehensive multiomics overview of each patient’s tumor, revealing tumor cell types, proteomics, and transcriptomic changes related to melanoma brain metastasis (MBM). Here, we have applied the HiRIEF pre-fractionation and tandem mass tags (TMT)-16plex based peptide quantification to generate proteomes of multiple neighboring regions within each MBM tumor tissue. PCA and Hierarchical clustering analysis illustrated higher inter-tumoral heterogeneity than intra-tumoral heterogeneity of MBM at the protein levels, as lesions from the same patients are grouped into a single cluster. The treatment-naive patient (P3) exhibited high intra-tumoral heterogeneity (ITH) compared to treated ones, with ITH levels varying across neighboring regions in patient tumors. Differential expression analysis highlighted enriched protein and gene clusters for all patient comparisons, including innate immune proteins, macrophage activation, T- and B-cell signaling, and key cancer pathways (e.g., epithelial-mesenchymal transition, cell adhesion, notch signaling, oxidative phosphorylation and cell cycle checkpoints). Genes involved in functional processes characteristic of MBM cell types, tumor-immune interactions, and signaling mechanisms were more highly correlated with their protein levels. Overall, our results provide a comprehensive spatial and molecular view of intra-tumoral and inter-tumoral heterogeneity in MBM.
Project description:Our study provides a comprehensive multiomics overview of each patient’s tumor, revealing tumor cell types, proteomics, and transcriptomic changes related to melanoma brain metastasis (MBM). Here, we have applied the HiRIEF pre-fractionation and tandem mass tags (TMT)-16plex based peptide quantification to generate proteomes of multiple neighboring regions within each MBM tumor tissue. PCA and Hierarchical clustering analysis illustrated higher inter-tumoral heterogeneity than intra-tumoral heterogeneity of MBM at the protein levels, as lesions from the same patients are grouped into a single cluster. The treatment-naive patient (P3) exhibited high intra-tumoral heterogeneity (ITH) compared to treated ones, with ITH levels varying across neighboring regions in patient tumors. Differential expression analysis highlighted enriched protein and gene clusters for all patient comparisons, including innate immune proteins, macrophage activation, T- and B-cell signaling, and key cancer pathways (e.g., epithelial-mesenchymal transition, cell adhesion, notch signaling, oxidative phosphorylation and cell cycle checkpoints). Genes involved in functional processes characteristic of MBM cell types, tumor-immune interactions, and signaling mechanisms were more highly correlated with their protein levels. Overall, our results provide a comprehensive spatial and molecular view of intra-tumoral and inter-tumoral heterogeneity in MBM.
Project description:Our study provides a comprehensive multiomics overview of each patient’s tumor, revealing tumor cell types, proteomics, and transcriptomic changes related to melanoma brain metastasis (MBM). Here, we have applied the HiRIEF pre-fractionation and tandem mass tags (TMT)-16plex based peptide quantification to generate proteomes of multiple neighboring regions within each MBM tumor tissue. PCA and Hierarchical clustering analysis illustrated higher inter-tumoral heterogeneity than intra-tumoral heterogeneity of MBM at the protein levels, as lesions from the same patients are grouped into a single cluster. The treatment-naive patient (P3) exhibited high intra-tumoral heterogeneity (ITH) compared to treated ones, with ITH levels varying across neighboring regions in patient tumors. Differential expression analysis highlighted enriched protein and gene clusters for all patient comparisons, including innate immune proteins, macrophage activation, T- and B-cell signaling, and key cancer pathways (e.g., epithelial-mesenchymal transition, cell adhesion, notch signaling, oxidative phosphorylation and cell cycle checkpoints). Genes involved in functional processes characteristic of MBM cell types, tumor-immune interactions, and signaling mechanisms were more highly correlated with their protein levels. Overall, our results provide a comprehensive spatial and molecular view of intra-tumoral and inter-tumoral heterogeneity in MBM.