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Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

43 Pages Posted: 25 Apr 2019 Sneak Peek Status: Review Complete

See all articles by Masahiro Hitomi

Masahiro Hitomi

Cleveland Clinic - Cellular and Molecular Medicine; Cleveland Clinic - Department of Molecular Medicine

Anastasia P. Chumakova

Cleveland Clinic - Cancer Impact Area

Daniel J. Silver

Cleveland Clinic - Department of Molecular Medicine

Arnon M. Knudsen

Odense University Hospital - Department of Pathology

W. Dean Pontius

Cleveland Clinic - Department of Molecular Medicine

Stephanie Murphy

Cleveland Clinic - Cancer Impact Area

Neha Anand

Cleveland Clinic - Cancer Impact Area

Bjarne W. Kristensen

Odense University Hospital - Department of Pathology

Justin D. Lathia

Cleveland Clinic - Cellular and Molecular Medicine; Cleveland Clinic - Department of Molecular Medicine; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

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Abstract

Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes remain to be determined. Using a fluorescent reporter for cell surface receptor distribution during mitosis, we found that ACD in glioblastoma CSCs generated a daughter cell with enhanced therapeutic resistance and increased co-inheritance of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR). Stimulation of both receptors maintained self-renewal under differentiation conditions. While p75NTR knockdown did not compromise CSC maintenance, therapeutic efficacy of EGFR inhibition was enhanced, indicating that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with co-enriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.

Keywords: Cancer Stem Cell, asymmetric cell division, therapeutic resistance, Glioblastoma

Suggested Citation

Hitomi, Masahiro and Chumakova, Anastasia P. and Silver, Daniel J. and Knudsen, Arnon M. and Pontius, W. Dean and Murphy, Stephanie and Anand, Neha and Kristensen, Bjarne W. and Lathia, Justin D., Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells (April 24, 2019). CELL-REPORTS-D-19-01320. Available at SSRN: https://ssrn.com/abstract=3377372 or http://dx.doi.org/10.2139/ssrn.3377372
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Masahiro Hitomi

Cleveland Clinic - Cellular and Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Anastasia P. Chumakova

Cleveland Clinic - Cancer Impact Area

United States

Daniel J. Silver

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Arnon M. Knudsen

Odense University Hospital - Department of Pathology

Denmark

W. Dean Pontius

Cleveland Clinic - Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Stephanie Murphy

Cleveland Clinic - Cancer Impact Area

United States

Neha Anand

Cleveland Clinic - Cancer Impact Area

United States

Bjarne W. Kristensen

Odense University Hospital - Department of Pathology

Denmark

Justin D. Lathia (Contact Author)

Cleveland Clinic - Cellular and Molecular Medicine ( email )

9500 Euclid Avenue
Cleveland, OH 44195
United States

Cleveland Clinic - Department of Molecular Medicine ( email )

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center ( email )

Cleveland, OH 44195
United States

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