Simple Aneuploidy Evades P53 Surveillance and Promotes Niche Factor-independent Growth in Human Intestinal Organoids

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2024 Jul 10

PMID 38985518

Authors

Blake A Johnson

Albert Z Liu

Tianhao Bi

Yi Dong

Taibo Li

Dingjingyu Zhou

Akshay Narkar

Yufei Wu

Sean X Sun

Tatianna C Larman

Jin Zhu

Rong Li

Affiliations

Soon will be listed here.

Abstract

Aneuploidy is nearly ubiquitous in tumor genomes, but the role of aneuploidy in the early stages of cancer evolution remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigated how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Previous work implicated p53 activation as a downstream response to aneuploidy induction. We found that simple aneuploidy, characterized by 1-3 gained or lost chromosomes, resulted in little or modest p53 activation and cell cycle arrest when compared with more complex aneuploid cells. Single-cell RNA sequencing analysis revealed that the degree of p53 activation was strongly correlated with karyotype complexity. Single-cell tracking showed that cells could continue to divide despite the observation of one to a few lagging chromosomes. Unexpectedly, colonoids with simple aneuploidy exhibited impaired differentiation after niche factor withdrawal. These findings demonstrate that simple aneuploid cells can escape p53 surveillance and may contribute to niche factor-independent growth of cancer-initiating colon stem cells.

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