Single cell spatial transcriptomics track the evolutionary hierarchy and microenvironment remodeling during breast...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• The transition from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is crucial for patient prognosis but poorly understood.
• Mechanisms driving invasion, including genetic alterations and tumor microenvironment (TME) interactions, require further elucidation.

Purpose of the Study:

• To map the spatial-molecular landscape of DCIS to IBC progression.
• To identify key drivers and cellular dynamics during breast cancer invasion.

Main Methods:

• Integration of single-cell RNA sequencing, spatial transcriptomics, and genomics from 28 patients with synchronous DCIS and IBC.
• Analysis of clonal expansion, transcriptional reprogramming, TME remodeling, and ligand-receptor interactions at the invasive front.

Main Results:

• Invasion is primarily driven by clonal expansion of existing DCIS subclones, with significant transcriptional and TME reprogramming.
• IBC cells show pronounced epithelial-mesenchymal transition and metabolic changes.
• Four distinct molecular stages (NMFT1-NMFT4) of basement membrane breach correlate with patient survival.

Conclusions:

• Breast cancer invasion is a process of transcriptional plasticity and TME remodeling, predominantly driven by clonal expansion rather than new driver mutations.
• A comprehensive spatial-molecular atlas of DCIS-IBC progression provides insights into invasion mechanisms and potential therapeutic targets.