Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties

Abstract

Missense-type mutant p53 plays a tumor-promoting role through gain-of-function (GOF) mechanism. In addition, the loss of wild-type TP53 through loss of heterozygosity (LOH) is widely found in cancer cells. However, malignant progression induced by cooperation of TP53 GOF mutation and LOH remains poorly understood. Here, we show that mouse intestinal tumors carrying Trp53 GOF mutation with LOH (AKTP M/LOH) are enriched in metastatic lesions when heterozygous Trp53 mutant cells (AKTP +/M) are transplanted. We show that Trp53 LOH is required for dormant cell survival and clonal expansion of cancer cells. Moreover, AKTP M/LOH cells show an increased in vivo tumor-initiating ability compared with AKTP Null and AKTP +/M cells. RNAseq analyses reveal that inflammatory and growth factor/ MAPK pathways are specifically activated in AKTP M/LOH cells, while the stem cell signature is upregulated in both AKTP M/LOH and AKTP Null cells. These results indicate that TP53/Trp53 LOH promotes TP53/Trp53 GOF mutation-driven metastasis through the activation of distinct pathway combination.

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

“…Cancer metastasis is a pathological process in which malignant cells spread from a primary site to a different site within the host's body [45,46]. The degradation of ECM plays a pivotal role in the process of metastasis.…”

Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation

“…The accumulation of driver mutations is understood to be responsible for the malignant progression of CRC 5 , and genome research has identified driver genes that are frequently mutated in CRC cells and are suspected of promoting each step of malignant progression 6,7 . Using genetic mouse models, we previously examined the link between specific combinations of driver mutations and each process of intestinal tumor progression, including submucosal invasion, epithelial mesenchymal transition (EMT)-like morphology, intravasation, and metastasis [8][9][10][11] . However, recent bioinformatics analyses have indicated that most driver mutations are accumulated in primary CRCs, suggesting that the metastasis process is not promoted by genetic alterations and subsequent clonal selection 12,13 .…”

“…To answer this question, we performed spleen transplantation experiments using a recently established organoid transplantation model 8,11 . In this model, mouse intestinal tumor-derived organoids carry various combinations of genetic alterations in driver genes.…”

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

“…Cancer metastasis is a pathological process which malignant cells spread from a primary site to a different site within the host's body [39,40]. The degradation of ECM plays a pivotal role in the process of metastasis.…”