Geospatial genetic evolution and phenotypic plasticity in triple-negative breast cancer

Area of Science:

• Genomics
• Cancer Biology
• Translational Research

Background:

• Triple-negative breast cancer (TNBC) metastasis is complex, with genotype-phenotype interactions poorly understood.
• Spatial heterogeneity within tumors influences metastatic evolution.
• Understanding these dynamics is crucial for developing effective TNBC therapies.

Purpose of the Study:

• To investigate spatial genomic and transcriptomic heterogeneity in TNBC.
• To explore the interplay between genotype and phenotype during TNBC metastasis.
• To identify novel biomarkers for TNBC prognosis and treatment.

Main Methods:

• Developed a pathology-guided geospatial genomic and transcriptomic sequencing workflow (pGeo-G&T-seq).
• Applied pGeo-G&T-seq to primary and metastatic TNBC specimens using laser capture microdissection (LCM).
• Integrated whole-exome, whole-genome, and whole-transcriptome sequencing with independent TNBC datasets.

Main Results:

• Uncovered spatial intratumoral heterogeneity with distinct genomic and transcriptomic patterns.
• Identified an oxidative phosphorylation (OXPHOS)-associated transcriptional state linked to poor prognosis and immunotherapy resistance.
• Observed that genetic ancestry influenced transcriptional stability and that metastatic clones retained phenotypic traits.

Conclusions:

• Genetic evolution and phenotypic retention drive TNBC spatial heterogeneity and metastasis.
• The pGeo-G&T-seq framework facilitates genotype-phenotype coupling analysis in intact tissues.
• The OXPHOS signature may aid TNBC patient stratification and guide future therapeutic strategies.