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 generated a daughter cell with enhanced therapeutic resistance and increased coenrichment of EGFR and neurotrophin receptor (p75NTR) from a glioblastoma CSC. Stimulation of both receptors antagonized differentiation induction and promoted self-renewal capacity. p75NTR knockdown enhanced the therapeutic efficacy of EGFR inhibition, indicating that coinheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. These data demonstrate that ACD produces progeny with coenriched growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population.
Highlights
Cancer stem cells (CSCs) drive tumor growth and are resistant to conventional therapies [1, 2]
We show that a functional consequence of Asymmetric cell division (ACD) is the ability to enrich prosurvival signaling activity by EGFR and nerve growth factor receptor (p75NTR) in 1 daughter cell
Based on the observation that CD133 is enriched in cholesterol-rich lipid rafts [14], we reasoned that a GFP fusion protein containing the N-terminus of Lyn that is enriched in lipid rafts through myristoylation/palmitoylation of its N-terminus [15] would report CD133 distribution between the 2 daughter cells during mitosis
Summary
Cancer stem cells (CSCs) drive tumor growth and are resistant to conventional therapies [1, 2]. Therapeutic resistance in CSCs has been attributed to multiple mechanisms, including active drug efflux pumps, enhanced DNA repair capacity, slow proliferation rate, and activation of key survival pathways [3,4,5]. While these resistance mechanisms have been identified, the mechanisms by which CSCs emerge, are maintained, and evolve as a result of therapies have yet to be determined. Since ACD can enrich fate-determining molecules in one of the emerging daughter cells, we hypothesized that this cellular mechanism may be leveraged in CSCs to generate therapeutically resistant progeny by concentrating prosurvival molecules to one daughter cell at the expense of the other
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