Single-Cell Expression Analysis of Ductal Carcinoma In Situ Identifies Complex Genotypic-Phenotypic Relationships...

Area of Science:

• Oncology
• Genomics
• Cell Biology

Background:

• Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer.
• Understanding the transition from DCIS to invasive cancer is crucial for early intervention.

Purpose of the Study:

• To identify molecular and cellular events driving the progression of DCIS to invasive breast cancer.
• To investigate the role of cellular heterogeneity and basement membrane integrity in invasion.

Main Methods:

• Single-cell RNA-sequencing (scRNA-seq) of DCIS lesions and matched normal breast tissue.
• Copy number variation (CNV) analysis to distinguish neoplastic cells.
• Phylogenetic and cell state classification analyses.
• In vitro modeling of DCIS invasion.

Main Results:

• Intratumoral heterogeneity in DCIS lesions showed significant gene expression differences.
• Estrogen receptor-negative DCIS exhibited altered cell state proportions compared to normal breast tissue.
• Basement membrane (BM) gene transcription was altered in specific epithelial cell states.
• Loss of COL4, a BM protein, in an in vitro model induced an invasive phenotype.

Conclusions:

• Breast cancer invasion from DCIS appears to be a loss-of-function event.
• Imbalances in cell populations critical for BM integrity contribute to invasion.
• Alterations in basement membrane components, particularly COL4, are implicated in the transition to invasive breast cancer.