Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

Zhou, Lin; Jilderda, Laura J; Foijer, Floris

doi:10.1098/rsob.200148

Cited by 18 publications

(8 citation statements)

References 136 publications

(185 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Gulay

Aoshima

Maekawa

et al. 2022

Sci Rep

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Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells. Tumor-associated macrophages are one of the major components of tumor microenvironment and crucial for cancer development. The presence and function of macrophages in HSA have not been studied because there is no syngeneic model for HSA. In this study, we evaluated two mouse HSA cell lines and one immortalized mouse endothelial cell line for their usefulness as syngeneic models for canine HSA. Our results showed that the ISOS-1 cell line developed tumors with similar morphology to canine HSA. ISOS-1 cells highly expressed KDM2B and had similar KDM2B target expression patterns with canine HSA. Moreover, we determined that in both ISOS-1 and canine HSA tumors, macrophages were present as a major constituent of the tumor microenvironment. These macrophages were positive for CD204, an M2 macrophage marker, and express PD-L1, an immune checkpoint molecule. Canine HSA with macrophages expressing PD-L1 had a smaller number of T-cells in tumor tissues than tumors with PD-L1 negative macrophages. ISOS-1-conditioned medium could induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line and mouse peritoneal macrophages. These results show that ISOS-1 can be used as a syngenic model for canine HSA and suggest that macrophages play an important role in immune evasion in HSA. Using the syngeneic mouse model for canine HSA, we can further study the role of immune cells in the pathology of HSA.

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Section: Discussionmentioning

confidence: 99%

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

Gulay

Aoshima

Maekawa

et al. 2022

Sci Rep

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“…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.…”

Section: Early Findings From Model Systemsmentioning

confidence: 99%

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

Jilderda

Zhou

Foijer

2021

Cells

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Chromosomal instability is the process of mis-segregation for ongoing chromosomes, which leads to cells with an abnormal number of chromosomes, also known as an aneuploid state. Induced aneuploidy is detrimental during development and in primary cells but aneuploidy is also a hallmark of cancer cells. It is therefore believed that premalignant cells need to overcome aneuploidy-imposed stresses to become tumorigenic. Over the past decade, some aneuploidy-tolerating pathways have been identified through small-scale screens, which suggest that aneuploidy tolerance pathways can potentially be therapeutically exploited. However, to better understand the processes that lead to aneuploidy tolerance in cancer cells, large-scale and unbiased genetic screens are needed, both in euploid and aneuploid cancer models. In this review, we describe some of the currently known aneuploidy-tolerating hits, how large-scale genome-wide screens can broaden our knowledge on aneuploidy specific cancer driver genes, and how we can exploit the outcomes of these screens to improve future cancer therapy.

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“…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 ].…”

Section: Phenotypic Effects Of Chromosomal Rearrangementsmentioning

confidence: 99%

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

Tang

Wen

et al. 2021

IJMS

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Chromosomal rearrangements comprise unbalanced structural variations resulting in gain or loss of DNA copy numbers, as well as balanced events including translocation and inversion that are copy number neutral, both of which contribute to phenotypic evolution in organisms. The exquisite genetic assay and gene editing tools available for the model organism Saccharomyces cerevisiae facilitate deep exploration of the mechanisms underlying chromosomal rearrangements. We discuss here the pathways and influential factors of chromosomal rearrangements in S. cerevisiae. Several methods have been developed to generate on-demand chromosomal rearrangements and map the breakpoints of rearrangement events. Finally, we highlight the contributions of chromosomal rearrangements to drive phenotypic evolution in various S. cerevisiae strains. Given the evolutionary conservation of DNA replication and recombination in organisms, the knowledge gathered in the small genome of yeast can be extended to the genomes of higher eukaryotes.

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Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

Cited by 18 publications

References 136 publications

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

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

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

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

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