On the role of p53 in the cellular response to aneuploidy

Abstract

SUMMARY Most solid tumors are aneuploid, and p53 has been implicated as the guardian of the euploid genome. Previous experiments using human cell lines showed that aneuploidy induction leads to p53 accumulation and p21-mediated G1 cell cycle arrest. We find that adherent 2-dimensional (2D) cultures of human immortalized or cancer cell lines activate p53 upon aneuploidy induction, whereas suspension cultures of a human lymphoid cell line undergo a p53-independent cell cycle arrest. Surprisingly, 3D human and mouse organotypic cultures from neural, intestinal, or mammary epithelial tissues do not activate p53 or arrest in G1 following aneuploidy induction. p53-deficient colon organoids have increased aneuploidy and frequent lagging chromosomes and multipolar spindles during mitosis. These data suggest that p53 may not act as a universal surveillance factor restricting the proliferation of aneuploid cells but instead helps directly or indirectly ensure faithful chromosome transmission likely by preventing polyploidization and influencing spindle mechanics.

Cancer tolerance to chromosomal instability is driven by Stat1 inactivation in vivo

“…Indeed, loss of p53 and CIN have been shown to collaborate in tumorigenesis in various models ( 12, 21, 22 ). However, the exact role of p53 in preventing the outgrowth of aneuploid cells is not fully understood, as for instance expression of a functional p53 does not impair propagation of all aneuploid cells per se ( 23, 24 ).…”

Deterministic evolution and stringent selection during pre-neoplasia

“…Expression of normal gastric cell type markers were evident in WT organoid cultures from each of the three donors, including pit mucosal cell markers (PMCs: MUC5AC, TFF1, TFF2, GKN2) in D1, enterocyte markers (FABP1, FABP2, ANPEP, PHGR1, KRT20) in D2 and gland mucosal cell (GMCs) markers (MUC6, PGC, TFF2, LYZ) in D3, despite low cell numbers (322, 1689 and 44 cells for D1-D3 respectively) (Fig. 3F-H, S11, Table S9) (22)(23)(24)(25). In contrast to WT cultures, the expression of gastric cell markers was heterogeneous in the Early, Mid and Late cultures TP53 deficient cultures (Fig.…”

“…Inactivation of TP53 is a nearly ubiquitous early event preceding numerical and structural chromosomal abnormalities (aneuploidy) in CIN GC ( 14 ). While most solid cancers are aneuploid due to a CIN phenotype with p53 loss permissive for CIN ( 18 ), whether TP53 loss can elicit aneuploidy remains controversial and is likely tissue type dependent ( 19 – 22 ). For example, TP53 deficiency or the introduction of TP53 hotspot missense mutations was sufficient for aneuploidy in non-transformed MCF10a mammary cells, whereas in colon organoids, dual inactivation of the APC gatekeeper tumor suppressor and TP53 was needed, emphasizing tissue specificities and context dependencies ( 23 – 25 ).…”

Chromosomal Instability, Selection and Competition: Factors That Shape the Level of Karyotype Intra-Tumor Heterogeneity

“…Cancers with no mutation in the TP53 gene often have other mutations in the TP53 pathway, e.g., in CDKN2A [ 69 ]. However, a recent study involving organoid cultures of TP53 deficient cells questioned the universality of TP53 to protect against aneuploidy [ 70 ]. Moreover, other genes, including BCL9L and MAPK14, have been implicated in suppressing tolerance to aneuploidy [ 71 , 72 ].…”