A mutant p53-dependent embryonic stem cell gene signature is associated with augmented tumorigenesis of stem cells

Gabriela Koifman, Yoav Shetzer, Shay Eizenberger, Hilla Solomon, Ron Rotkopf, Alina Molchadsky, Giuseppe Lonetto, Naomi Goldfinger, Varda Rotter

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Mutations in the tumor suppressor p53 are the most frequent alterations inhuman cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-offunction (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse. Here we show that in vitro cultivation of tumors derived from mutant p53 murine bone marrow mesenchymal stem cells (MSC) gives rise to aggressive tumor lines (TL). These MSC-TLs exhibited CSC features as displayed by their augmented oncogenicity and high expression of CSC markers. Comparative analyses between MSC-TL with their parental mutant p53 MSC allowed for identification of the molecular events underlying their tumorigenic properties, including an embryonic stem cell (ESC) gene signature specifically expressed in MSC-TLs. Knockout of mutant p53 led to a reduction in tumor development and tumorigenic cell frequency, which was accompanied by reduced expression of CSC markers and the ESC MSC-TL signature. In human cancer, MSC-TL ESC signature-derived genes correlated with poor patient survival and were highly expressed in human tumors harboring p53 hotspot mutations. These data indicate that the ESC gene signature-derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.

Original languageEnglish
Pages (from-to)5833-5847
Number of pages15
JournalCancer Research
Volume78
Issue number20
DOIs
StatePublished - 15 Oct 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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