Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers

Abstract

Emerging notion in carcinogenesis ascribes tumor initiation and aggressiveness to cancer stem cells (CSCs). Specifically, colorectal cancer (CRC) development was shown to be compatible with CSCs hypothesis. Mutations in p53 are highly frequent in CRC, and are known to facilitate tumor development and aggressiveness. Yet, the link between mutant p53 and colorectal CSCs is not well-established. In the present study, we set to examine whether oncogenic mutant p53 proteins may augment colorectal CSCs phenotype. By genetic manipulation of mutant p53 in several cellular systems, we demonstrated that mutant p53 enhances colorectal tumorigenesis. Moreover, mutant p53-expressing cell lines harbor larger subpopulations of cells highly expressing the known colorectal CSCs markers: CD44, Lgr5, and ALDH. This elevated expression is mediated by mutant p53 binding to CD44, Lgr5, and ALDH1A1 promoter sequences. Furthermore, ALDH1 was found to be involved in mutant p53-dependent chemotherapy resistance. Finally, analysis of ALDH1 and CD44 in human CRC biopsies indicated a positive correlation between their expression and the presence of oncogenic p53 missense mutations. These findings suggest novel insights pertaining the mechanism by which mutant p53 enhances CRC development, which involves the expansion of CSCs sub-populations within CRC tumors, and underscore the importance of targeting these sub-populations for CRC therapy.

Concordance between TP53 alterations in blood and tissue: impact of time interval, biopsy site, cancer type and circulating tumor DNA burden

“…Our analysis revealed that the most common alterations detected in both tissue biopsy and blood‐derived ctDNA were in the TP53 gene (49.7% and 36.7%, respectively); altogether, 59.6% of patients had ≥ 1 TP53 alteration in blood, tissue, or both. These frequencies are consistent with previous studies in the literature (Kadia et al , 2016; Robles and Harris, 2010; Said et al , 2013, 2014; Schwaederlé et al , 2017; Solomon et al , 2018; Soussi, et al , 2006; Sun et al , 2018; Villaflor et al , 2016). Other common alterations in ctDNA, tissue, or both were in the KRAS (23.3%), CDK2A/B (20.6%), EGFR (17.6%), and PIK3CA genes (15.5%) (Fig.…”

“…Blood‐derived ctDNA and tissue DNA are frequently analyzed by NGS for determining diagnosis, prognosis, and treatment. Previous studies have described the frequency of TP53 alteration detection using tissue DNA and blood‐derived NGS separately (Robles and Harris, 2010; Said et al , 2013, 2014; Solomon et al , 2018; Soussi, et al , 2006; Sun et al , 2018). However, there is a paucity of research determining concordance between TP53 alterations in blood‐derived ctDNA vs tissue DNA.…”

“…With the recent increase in clinical oncology research moving to more minimal invasive and efficient technologies, blood‐derived ctDNA testing has become more appealing. Studies have revealed that next‐generation sequencing (NGS) frequently detects TP53 alterations in both tissue and ctDNA (Robles and Harris, 2010; Said et al , 2013, 2014; Solomon et al , 2018; Soussi, et al , 2006; Sun et al , 2018). Herein, we examine the impact of temporal separation on concordance between TP53 mutations in blood vs tissue, as well as associations between concordance and biopsy site, histology, and %ctDNA in 433 patients with diverse cancer types who underwent NGS of tissue and plasma‐derived ctDNA.…”

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

“…3L ; Supplementary Table S6 ). Specifically, these include the CD44 and MAP3K8 transcripts, which have been shown to be positively regulated by mutant p53 (36,37). Thus, the p53 poly(A) SNP not only results in allelic-differences in mutant p53 expression, but also in one of its oncogenic properties.…”

Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

“…The vast majority of driver mutations affect the p53 DNA binding domain (DBD) (Sameer 2013). TP53 mutations can abolish cell control functions and confer gain-of-function properties (Solomon et al 2018). Impairment of p53 function results in uncontrolled proliferation in the critical adenoma-adenocarcinoma transition stage (Eshghifar et al 2017).…”