Transcript and protein signatures derived from shared molecular interactions across cancers are associated with...

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment Research

Background:

• Shared cancer mechanisms are crucial for improving therapeutic strategies and patient prognosis.
• Understanding cell-cell interactions (CCIs) within the tumor microenvironment is key to advancing cancer treatment.

Purpose of the Study:

• To identify shared CCIs across multiple solid cancers.
• To assess the association of these shared CCIs with cancer mortality.

Main Methods:

• NicheNet analysis of single-cell RNA sequencing data from breast, colon, liver, lung, and ovarian cancers to identify CCIs.
• Construction of a shared multi-cellular tumor model (shared-MCTM) from identified CCIs.
• Validation of a derived gene signature in The Cancer Genome Atlas (TCGA) and UK Biobank (UKBB) cohorts at mRNA and protein levels, assessing association with 10-year all-cause mortality using Cox proportional hazards models.

Main Results:

• A shared-MCTM was successfully derived, yielding a gene signature prominently involving matrix cancer-associated fibroblasts (mCAFs).
• The gene signature showed significant differential expression in multiple cancers compared to controls at both mRNA and protein levels in independent cohorts.
• The signature was significantly associated with cancer patient mortality in both TCGA and UKBB cohorts, with notable variations in risk observed for specific cancers (e.g., brain, ovarian) and sexes.

Conclusions:

• A novel gene signature derived from a shared-MCTM effectively represents common CCIs across diverse cancers.
• The study highlights the critical regulatory role of mCAFs within the tumor microenvironment.
• The identified gene signature demonstrates pathogenic relevance and prognostic value for cancer mortality, supported by robust validation in large independent cohorts.