KRAS mutation is the most frequent oncogenic aberration in colorectal cancer (CRC). The molecular mechanism and clinical implications of KRAS mutation in CRC remain unclear and show high heterogeneity within these tumors. Methods: We harnessed the multi-omics data (genomic, transcriptomic, proteomic, and phosphoproteomic etc.) of KRAS-mutant CRC tumors and performed unsupervised clustering to identify proteomics-based subgroups and molecular characterization. Results: In-depth analysis of the tumor microenvironment by single-cell transcriptomic revealed the cellular landscape of KRAS-mutant CRC tumors and identified the specific cell subsets with KRAS mutation. Integrated multi-omics analyses separated the KRAS-mutant tumors into two distinct molecular subtypes, termed KRAS-M1 (KM1) and KRAS-M2 (KM2). The two subtypes had a similar distribution of mutated residues in KRAS (G12D/V/C etc.) but were characterized by distinct features in terms of prognosis, genetic alterations, microenvironment dysregulation, biological phenotype, and potential therapeutic approaches. Proteogenomic analyses revealed that the EMT, TGF-β and angiogenesis pathways were enriched in the KM2 subtype and that the KM2 subtype was associated with the mesenchymal phenotype-related CMS4 subtype, which indicated stromal invasion and worse prognosis. The KM1 subtype was characterized predominantly by activation of the cell cycle, E2F and RNA transcription and was associated with the chromosomal instability (CIN)-related ProS-E proteomic subtype, which suggested cyclin-dependent features and better survival outcomes. Moreover, drug sensitivity analyses based on three compound databases revealed subgroup-specific agents for KM1 and KM2 tumors. Conclusions: This study clarifies the molecular heterogeneity of KRAS-mutant CRC and reveals new biological subtypes and therapeutic possibilities for these tumors.
Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren’s histological classification. Integrin β1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.
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