Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

Abstract

Aneuploidy, an irregular number of chromosomes in cells, is a hallmark feature of cancer. Aneuploidy results from chromosomal instability (CIN) and occurs in almost 90% of all tumours. While many cancers display an ongoing CIN phenotype, cells can also be aneuploid without displaying CIN. CIN drives tumour evolution as ongoing chromosomal missegregation will yield a progeny of cells with variable aneuploid karyotypes. The resulting aneuploidy is initially toxic to cells because it leads to proteotoxic and metabolic stress, cell cycle arrest, cell death, immune cell activation and further genomic instability. In order to overcome these aneuploidy-imposed stresses and adopt a malignant fate, aneuploid cancer cells must develop aneuploidy-tolerating mechanisms to cope with CIN. Aneuploidy-coping mechanisms can thus be considered as promising therapeutic targets. However, before such therapies can make it into the clinic, we first need to better understand the molecular mechanisms that are activated upon aneuploidization and the coping mechanisms that are selected for in aneuploid cancer cells. In this review, we discuss the key biological responses to aneuploidization, some of the recently uncovered aneuploidy-coping mechanisms and some strategies to exploit these in cancer therapy.

Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages

“…ISOS-1 possessed similar molecular features with canine HSA such as high KDM2B expression and ubiquitination of its target H2AK119, whereas high KDM2B expression and high H2AK119ub1 level were not detected in UV♀2 and LEII. ISOS-1 cells were aneuploid, which implies that they have severe DNA stresses leading to apoptotic cell death 19 . ISOS-1 cells probably overcome cell deaths by deactivating a pro-apoptotic protein ERK1/2 and activating DNA repair proteins such as c-FOS and γH2A.X.…”

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

“…These contradicting observations are frequently referred to as the 'aneuploidy paradox' [9] and suggest that aneuploid cells need to overcome certain barriers to become malignant. As overcoming these stresses might be an important step during tumorigenesis, modulators of aneuploidyimposed stresses are considered attractive targets for therapeutic intervention [31]. Below, we discuss some of these stresses and elaborate on how these findings have broadened our knowledge on how cancer cells deal with aneuploidy.…”

Origin, Regulation, and Fitness Effect of Chromosomal Rearrangements in the Yeast Saccharomyces cerevisiae

“…Thirdly, rearrangements reorganize the 3D architecture of chromosomes, which in turn can modify the expression of genetic information [ 6 , 7 ]. Lastly, cells with large deletions/duplications, such as aneuploidy cells, may suffer from aneuploidy-associated stresses [ 139 , 140 ]. We refer the reader interested in the phenotypic effects of whole chromosome aneuploidy to the reviews [ 44 , 126 ].…”