Path to Clonal Theranostics in Luminal Breast Cancers

Area of Science:

• Proteomics and Cancer Biology
• Mass Spectrometry Imaging
• Drug Discovery

Background:

• Tumor heterogeneity presents a significant challenge in breast cancer treatment, leading to drug resistance.
• Identifying functionally distinct tumor subpopulations is crucial for developing targeted therapies and achieving clonal theranostics.
• Current approaches often overlook the complexity of intra-tumor heterogeneity.

Purpose of the Study:

• To perform an unsupervised, spatially resolved proteomic analysis of early luminal breast cancer clones.
• To identify novel protein targets and pathways associated with tumor heterogeneity for drug discovery.
• To compare clonal proteomic data with existing databases (TCGA, BC360, CDx) to highlight unique molecular insights.

Main Methods:

• Unsupervised, label-free, spatially resolved shotgun proteomics guided by MALDI mass spectrometry imaging (MSI).
• Analysis of 124 selected tumor clonal areas from early luminal breast cancers, stroma, and metastases.
• Comparative analysis with TCGA, BC360, and CDx datasets to identify unique pathways and drug targets.

Main Results:

• Identified 2868 proteins, with distinct protein classes compared to TCGA transcriptomic data.
• Discovered 139 pathways in the clonal proteome, with only 50-68% overlap with other datasets.
• Found 35 unique anticancer drug matches and a higher number of non-anticancer drug interactions, suggesting drug repurposing potential.

Conclusions:

• Spatially resolved clonal proteomics provides non-redundant molecular knowledge compared to bulk analysis or transcriptomics.
• The identified protein targets and pathways offer promising candidates for breast cancer drug discovery and repurposing.
• This clone-tailored approach enhances the understanding of tumor heterogeneity for developing more effective theranostic strategies.