Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

Abstract

Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy.

Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non–Cell Autonomous Liver Carcinogenesis

“…These findings suggested that HPCs in LiKM mice extracted as organoids harbored characteristics of cancer cells. Chromosomal abnormalities are one of the most common forms of genomic instability in cancers ( 34 ). This instability could substantially affect cell physiology and phenotypes, including cell-cycle regulation, metabolism, and protein homeostasis, which might drive carcinogenesis ( 34 ).…”

“…Chromosomal abnormalities are one of the most common forms of genomic instability in cancers ( 34 ). This instability could substantially affect cell physiology and phenotypes, including cell-cycle regulation, metabolism, and protein homeostasis, which might drive carcinogenesis ( 34 ). Whereas chromosomal abnormalities might contribute to the tumorigenicity of LiKM organoids, little is known to date about the genetic drivers of HPC-derived HCC ( 29 ).…”

Pan-Cancer Analysis and Experimental Validation Identify ACOT7 as a Novel Oncogene and Potential Therapeutic Target in Lung Adenocarcinoma

“…Our findings also suggested that ACOT7 was significantly associated with genes encoding tumor immunity factors. Previous studies reported that the viability and function of cancer cells and immune cells depend on the cellular metabolism, which is heavily influenced by the TME [ 60 , 61 , 62 ]. ACOT7 might alter the metabolism of cancer cells by regulating TME-related pathways.…”

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“…These changes can be accompanied by hyperactivation of proto-oncogenes and hypoactivation or loos of function of tumor suppressor genes (Weston and Harris, 2003;Mendelsohn et al, 2014). Additionally, karyotypic variations, aneuploidy (Sansregret and Swanton, 2017), and polyploidy are observed at this step (Baudoin and Bloomfield, 2021). As the disease progresses, the cells would have a strong tendency to separate from the colony and impinge to other tissues in the body through different mechanisms underlying the metastasis process.…”