Deep visual multi-omics profiling reveals mechanisms that underly cancer cell differentiation and aggressiveness in clear cell renal cell carcinoma

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) exhibits significant intra-tumoral heterogeneity (ITH) at both morphological and genetic levels, complicating treatment and contributing to disease progression. Among these, rhabdoid ccRCCs stand out as highly aggressive tumors distinguished by cells with unique morphological features and poor clinical outcomes3. However, the relationship between distinct cellular morphologies, specific molecular alterations, and their impact on tumor behavior remains poorly understood. Unraveling the molecular underpinnings of cells with clinically relevant histological features will be critical for developing more effective treatments targeting key cellular subsets responsible for tumor progression. In this study, we integrated advanced AI-based image analysis with single-cell isolation and multi-omics profiling to dissect the link between clinically relevant morphological and molecular features of ccRCC cells. Using a novel digital pathology workflow, we precisely quantified low-grade, high-grade, and rhabdoid morphologies in ccRCC diagnostic images. By isolating two sets of 1,000 morphologically distinct cells for detailed mRNA and protein expression analyses we uncovered increasing dysregulation of cancer-relevant molecular pathways associating with higher histopathological grades. Rhabdoid ccRCC cells (grade 4) exhibited a distinct molecular profile, including upregulated FOXM1-driven proliferation, disrupted cell-matrix interactions, and enhanced immune evasion pathways. Despite high T-cell infiltration in rhabdoid areas, we identified a rhabdoid cell-specific immunosuppressive network driven by cytokines, IFN-beta, and integrin signaling, likely contributing to T-cell exhaustion. These findings provide a basis for novel combination treatment strategies aimed at enhancing immune checkpoint inhibitor (ICI) efficacy in patients with aggressive rhabdoid ccRCC.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Kidney

DISEASE(S): Kidney Cancer

SUBMITTER: Dorothea Rutishauser  

LAB HEAD: Dorothea Rutishauser

PROVIDER: PXD061011 | Pride | 2025-02-21

REPOSITORIES: pride