In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example

Hana Golan, Rachel Shukrun, Revital Caspi, Einav Vax, Naomi Pode-Shakked, Sanja Goldberg, Oren Pleniceanu, Dekel D. Bar-Lev, Michal Mark-Danieli, Sara Pri-Chen, Jasmine Jacob-Hirsch, Itamar Kanter, Ariel Trink, Ginette Schiby, Ron Bilik, Tomer Kalisky, Orit Harari-Steinberg, Amos Toren, Benjamin Dekel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer stem cell (CSC) identification relies on transplantation assays of cell subpopulations sorted from fresh tumor samples. Here, we attempt to bypass limitations of abundant tumor source and predetermined immune selection by in vivo propagating patient-derived xenografts (PDX) from human malignant rhabdoid tumor (MRT), a rare and lethal pediatric neoplasm, to an advanced state in which most cells behave as CSCs. Stemness is then probed by comparative transcriptomics of serial PDXs generating a gene signature of epithelial to mesenchymal transition, invasion/motility, metastasis, and self-renewal, pinpointing putative MRT CSC markers. The relevance of these putative CSC molecules is analyzed by sorting tumorigenic fractions from early-passaged PDX according to one such molecule, deciphering expression in archived primary tumors, and testing the effects of CSC molecule inhibition on MRT growth. Using this platform, we identify ALDH1 and lysyl oxidase (LOX) as relevant targets and provide a larger framework for target and drug discovery in rare pediatric cancers. Golan et al. demonstrate that long-term propagation of human MRT xenografts robustly enriches for cancer stem cell frequency. This was exploited in turn for the identification of potential therapeutic targets in MRT such as lysyl oxidase and disclosed a platform to identify CSC targets in other rare pediatric tumors for which novel therapeutics are sought.

Original languageEnglish
Pages (from-to)795-810
Number of pages16
JournalStem Cell Reports
Volume11
Issue number3
DOIs
StatePublished - 11 Sep 2018

Funding

FundersFunder number
Zeiring Foundation
Israel Cancer Research FundPG-14-112
Israel Cancer Association20150916

    Keywords

    • ALDH1
    • LOX inhibition
    • MRT
    • PDX
    • cancer stem cells
    • stem cells
    • targeted therapy

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