Single-cell and Bulk RNA-Seq Analyses Reveal TOMM7-mediated Multi-cell Death Mechanisms Driving Muscle-invasive...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Muscle-invasive bladder cancer (MIBC) presents a significant clinical challenge due to its high malignancy and poor prognosis.
• Single-cell RNA sequencing (scRNA-seq) offers novel avenues to explore the molecular heterogeneity and progression mechanisms of MIBC.

Purpose of the Study:

• To identify key molecular drivers and dysregulated pathways in MIBC.
• To develop a prognostic model for stratifying MIBC patients and predicting treatment response.
• To investigate the functional role and therapeutic potential of TOMM7 in MIBC.

Main Methods:

• Construction of a single-cell atlas of bladder cancer (BCa) to identify MIBC-specific epithelial subclusters (Epi_MIBC).
• Characterization of key transcription factors and cell death pathways.
• Development and validation of a prognostic model (MIBC.CDGs) using machine learning.
• In vitro experiments and molecular docking to assess TOMM7 function and druggability.

Main Results:

• The MIBC-related cell death score (MIBC.CDS) effectively stratified patient prognosis and predicted immunotherapy response.
• Multiple cell death pathways, including apoptosis, autophagy, mitophagy, cuproptosis, and ferroptosis, were found to be activated in MIBC.
• TOMM7 knockdown inhibited proliferation, invasion, and migration in T24 cells, confirming its oncogenic role.
• Sorafenib was identified as a potential therapeutic agent targeting TOMM7 via molecular docking.

Conclusions:

• Dysregulation of cell death pathways is critical in MIBC progression, with TOMM7 acting as a novel oncogenic regulator.
• The MIBC.CDS shows promise for prognostic evaluation and therapeutic stratification in MIBC patients.
• TOMM7-targeted therapy, potentially with sorafenib, represents a new strategy for MIBC treatment.