Microfluidic single-cell migration chip reveals insights into the impact of extracellular matrices on cell movement

Zhou, Mengli; Ma, Yushu; Rock, Edwin C.; Chiang, Chun-Cheng; Luker, Kathryn E.; Luker, Gary D.; Chen, Yu-Chih

doi:10.1039/d3lc00651d

Cited by 2 publications

References 109 publications

(136 reference statements)

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

Zhou,

Ma,

Chiang

et al. 2023

Commun Biol

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Considerable evidence suggests that breast cancer therapeutic resistance and relapse can be driven by polyploid giant cancer cells (PGCCs). The number of PGCCs increases with the stages of disease and therapeutic stress. Given the importance of PGCCs, it remains challenging to eradicate them. To discover effective anti-PGCC compounds, there is an unmet need to rapidly distinguish compounds that kill non-PGCCs, PGCCs, or both. Here, we establish a single-cell morphological analysis pipeline with a high throughput and great precision to characterize dynamics of individual cells. In this manner, we screen a library to identify promising compounds that inhibit all cancer cells or only PGCCs (e.g., regulators of HDAC, proteasome, and ferroptosis). Additionally, we perform scRNA-Seq to reveal altered cell cycle, metabolism, and ferroptosis sensitivity in breast PGCCs. The combination of single-cell morphological and molecular investigation reveals promising anti-PGCC strategies for breast cancer treatment and other malignancies.

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

Zhou,

Ma,

Chiang

et al. 2023

Commun Biol

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High-Throughput Empirical and Virtual Screening to Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

Ma,

Shih,

Cheng

et al. 2024

Preprint

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Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole-genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2,726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirically testing all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacy in silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated two compounds as potent PGCC inhibitors. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer.

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Microfluidic single-cell migration chip reveals insights into the impact of extracellular matrices on cell movement

Abstract: Cell migration is a complex process that plays a crucial role in normal physiology and pathologies such as cancer, autoimmune diseases, and mental disorders. Conventional cell migration assays face limitations...

Cited by 2 publications

References 109 publications

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

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

High-Throughput Empirical and Virtual Screening to Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

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