Identification of a Mutant P53-dependent Embryonic Gene Signature Associated with Augmented Tumorigenesis of Stem Cells

Mutations in the tumor suppressor p53 are the most frequent alteration in human cancers. These mutations include p53 inactivating mutations and oncogenic gain of function (GOF) mutations that endow the p53 proteins with capabilities to promote tumor progression. One of the main challenges in cancer therapy is targeting stemness features and cancer stem cells (CSCs) 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 (BM) mesenchymal stem cells (MSCs), gave rise to aggressive tumor lines (TLs). These MSC-TLs exhibited CSC features as displayed by their augmented oncogenicity and high CSC markers expression. Comparative analyses between MSC-TLs with their parental cells, mutant p53 MSCs, can serve as a unique experimental system permitting the unveiling of the molecular events underlying their tumorigenic properties. Indeed, transcriptional comparison identified an Embryonic Stem Cell (ESC) gene signature, specifically expressed in the MSC-TLs. Importantly, knocking-out mutant p53 led to a reduction in tumor development and tumorigenic cell frequency that was accompanied by a reduction in the expression of the identified ESC MSC-TLs signature. Thus, unveiling a novel role of mutant p53 in facilitating cancer stemness traits. Interestingly, MSC-TLs ESC signature derived genes correlated with poor patient survival in human cancers. Furthermore, Pan-cancer expression analysis indicated that the ESC signature derived genes were highly expressed in human tumors harboring p53 hotspot mutations. The ESC gene signature derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.