Single-cell morphological and transcriptome analysis unveil inhibitors of polyploid giant breast cancer cells in...

Area of Science:

• Oncology
• Cell Biology
• Drug Discovery

Background:

• Polyploid giant cancer cells (PGCCs) are implicated in breast cancer therapeutic resistance and relapse.
• The prevalence of PGCCs increases with disease stage and under therapeutic pressure.
• Eradicating PGCCs remains a significant challenge in cancer treatment.

Purpose of the Study:

• To develop a high-throughput method for distinguishing compounds that selectively kill PGCCs, non-PGCCs, or both.
• To screen a compound library for novel anti-PGCC agents.
• To investigate the molecular characteristics of breast cancer PGCCs.

Main Methods:

• Establishment of a high-throughput single-cell morphological analysis pipeline.
• Screening of a compound library to identify inhibitors of PGCCs or all cancer cells.
• Single-cell RNA sequencing (scRNA-Seq) to analyze cell cycle, metabolism, and ferroptosis in PGCCs.

Main Results:

• Identification of compounds targeting HDAC, proteasome, and ferroptosis pathways as potential anti-PGCC agents.
• scRNA-Seq revealed alterations in cell cycle, metabolism, and ferroptosis sensitivity in breast PGCCs.
• A combined morphological and molecular approach identified promising anti-PGCC strategies.

Conclusions:

• The developed pipeline enables rapid identification of effective anti-PGCC compounds.
• Targeting specific pathways like HDAC, proteasome, and ferroptosis shows promise for eradicating PGCCs.
• This research offers new therapeutic strategies for breast cancer and other malignancies driven by PGCCs.