Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator

Yu Chih Chen, Brock Humphries, Riley Brien, Anne E. Gibbons, Yu Ting Chen, Tonela Qyli, Henry R. Haley, Matthew E. Pirone, Benjamin Chiang, Annie Xiao, Yu Heng Cheng, Yi Luan, Zhixiong Zhang, Jason Cong, Kathryn E. Luker, Gary D. Luker, Euisik Yoon

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Isolation of tumor-initiating cells currently relies on markers that do not reflect essential biologic functions of these cells. We proposed to overcome this limitation by isolating tumor-initiating cells based on enhanced migration, a function tightly linked to tumor-initiating potential through epithelial-to-mesenchymal transition (EMT). We developed a high-throughput microfluidic migration platform with automated cell tracking software and facile recovery of cells for downstream functional and genetic analyses. Using this device, we isolated a small subpopulation of migratory cells with significantly greater tumor formation and metastasis in mouse models. Whole transcriptome sequencing of migratory versus non-migratory cells from two metastatic breast cancer cell lines revealed a unique set of genes as key regulators of tumor-initiating cells. We focused on phosphatidylserine decarboxylase (PISD), a gene downregulated by 8-fold in migratory cells. Breast cancer cells overexpressing PISD exhibited reduced tumor-initiating potential in a high-throughput microfluidic mammosphere device and mouse xenograft model. PISD regulated multiple aspects of mitochondria, highlighting mitochondrial functions as therapeutic targets against cancer stem cells. This research establishes not only a novel microfluidic technology for functional isolation of tumor-initiating cells regardless of cancer type, but also a new approach to identify essential regulators of these cells as targets for drug development.

Original languageEnglish
Article number244
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Microfluidics
Neoplastic Stem Cells
Lab-On-A-Chip Devices
Neoplasms
Cell Tracking
Breast Neoplasms
Epithelial-Mesenchymal Transition
phosphatidylserine decarboxylase
Transcriptome
Heterografts
Genes
Mitochondria
Down-Regulation
Software
Neoplasm Metastasis
Technology
Cell Line
Equipment and Supplies
Research
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • General

Cite this

Chen, Yu Chih ; Humphries, Brock ; Brien, Riley ; Gibbons, Anne E. ; Chen, Yu Ting ; Qyli, Tonela ; Haley, Henry R. ; Pirone, Matthew E. ; Chiang, Benjamin ; Xiao, Annie ; Cheng, Yu Heng ; Luan, Yi ; Zhang, Zhixiong ; Cong, Jason ; Luker, Kathryn E. ; Luker, Gary D. ; Yoon, Euisik. / Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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abstract = "Isolation of tumor-initiating cells currently relies on markers that do not reflect essential biologic functions of these cells. We proposed to overcome this limitation by isolating tumor-initiating cells based on enhanced migration, a function tightly linked to tumor-initiating potential through epithelial-to-mesenchymal transition (EMT). We developed a high-throughput microfluidic migration platform with automated cell tracking software and facile recovery of cells for downstream functional and genetic analyses. Using this device, we isolated a small subpopulation of migratory cells with significantly greater tumor formation and metastasis in mouse models. Whole transcriptome sequencing of migratory versus non-migratory cells from two metastatic breast cancer cell lines revealed a unique set of genes as key regulators of tumor-initiating cells. We focused on phosphatidylserine decarboxylase (PISD), a gene downregulated by 8-fold in migratory cells. Breast cancer cells overexpressing PISD exhibited reduced tumor-initiating potential in a high-throughput microfluidic mammosphere device and mouse xenograft model. PISD regulated multiple aspects of mitochondria, highlighting mitochondrial functions as therapeutic targets against cancer stem cells. This research establishes not only a novel microfluidic technology for functional isolation of tumor-initiating cells regardless of cancer type, but also a new approach to identify essential regulators of these cells as targets for drug development.",
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Chen, YC, Humphries, B, Brien, R, Gibbons, AE, Chen, YT, Qyli, T, Haley, HR, Pirone, ME, Chiang, B, Xiao, A, Cheng, YH, Luan, Y, Zhang, Z, Cong, J, Luker, KE, Luker, GD & Yoon, E 2018, 'Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator', Scientific reports, vol. 8, no. 1, 244. https://doi.org/10.1038/s41598-017-18610-5

Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator. / Chen, Yu Chih; Humphries, Brock; Brien, Riley; Gibbons, Anne E.; Chen, Yu Ting; Qyli, Tonela; Haley, Henry R.; Pirone, Matthew E.; Chiang, Benjamin; Xiao, Annie; Cheng, Yu Heng; Luan, Yi; Zhang, Zhixiong; Cong, Jason; Luker, Kathryn E.; Luker, Gary D.; Yoon, Euisik.

In: Scientific reports, Vol. 8, No. 1, 244, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - Functional Isolation of Tumor-Initiating Cells using Microfluidic-Based Migration Identifies Phosphatidylserine Decarboxylase as a Key Regulator

AU - Chen, Yu Chih

AU - Humphries, Brock

AU - Brien, Riley

AU - Gibbons, Anne E.

AU - Chen, Yu Ting

AU - Qyli, Tonela

AU - Haley, Henry R.

AU - Pirone, Matthew E.

AU - Chiang, Benjamin

AU - Xiao, Annie

AU - Cheng, Yu Heng

AU - Luan, Yi

AU - Zhang, Zhixiong

AU - Cong, Jason

AU - Luker, Kathryn E.

AU - Luker, Gary D.

AU - Yoon, Euisik

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Isolation of tumor-initiating cells currently relies on markers that do not reflect essential biologic functions of these cells. We proposed to overcome this limitation by isolating tumor-initiating cells based on enhanced migration, a function tightly linked to tumor-initiating potential through epithelial-to-mesenchymal transition (EMT). We developed a high-throughput microfluidic migration platform with automated cell tracking software and facile recovery of cells for downstream functional and genetic analyses. Using this device, we isolated a small subpopulation of migratory cells with significantly greater tumor formation and metastasis in mouse models. Whole transcriptome sequencing of migratory versus non-migratory cells from two metastatic breast cancer cell lines revealed a unique set of genes as key regulators of tumor-initiating cells. We focused on phosphatidylserine decarboxylase (PISD), a gene downregulated by 8-fold in migratory cells. Breast cancer cells overexpressing PISD exhibited reduced tumor-initiating potential in a high-throughput microfluidic mammosphere device and mouse xenograft model. PISD regulated multiple aspects of mitochondria, highlighting mitochondrial functions as therapeutic targets against cancer stem cells. This research establishes not only a novel microfluidic technology for functional isolation of tumor-initiating cells regardless of cancer type, but also a new approach to identify essential regulators of these cells as targets for drug development.

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