Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis

Tang, Yun‐Chi; Yuwen, Hui; Wang, Kaiying; Bruno, Peter M.; Bullock, Kevin; Deik, Amy; Santaguida, Stefano; Trakala, Marianna; Pfau, Sarah J.; Zhong, Na; Huang, Tao; Wang, Lan; Clish, Clary B.; Hemann, Michael T.; Amon, Angelika

doi:10.1158/0008-5472.can-17-0049

Cited by 43 publications

(36 citation statements)

References 54 publications

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“…Recent studies have reported the successful targeting of metabolic vulnerabilities which are specific to the tissue-of-origin 16,44 or stem from chromosomal abnormalities 45,46 . We therefore used cBioportal 47,48 to determine copy number amplifications in metabolic genes within our MEC-specific networks in order to identify novel subtype-specific metabolic targets.…”

Section: Resultsmentioning

confidence: 99%

Mammary epithelial cells have lineage-restricted metabolic identities

Mahendralingam

Aliar

Casey

et al. 2019

Preprint

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1Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast 2 cancer is not a disease of a singular origin. Multiple epithelial populations serve as the 3 culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the 4 metabolic network of normal mammary epithelial cells is limited. Here, we show that 5 mammary populations have cell type-specific metabolic programs. Primary human breast 6 cell proteomes of basal, luminal progenitor, and mature luminal populations revealed their 7 unique enrichment of metabolic proteins. Luminal progenitors had higher abundance of 8 electron transport chain subunits and capacity for oxidative phosphorylation, whereas 9 basal cells were more glycolytic. Targeting oxidative phosphorylation and glycolysis with 10 inhibitors exposed distinct metabolic vulnerabilities of the mammary lineages. 11 Computational analysis indicated that breast cancer subtypes retain metabolic features 12 of their putative cell-of-origin. Lineage-restricted metabolic identities of normal mammary 13 cells partly explain breast cancer metabolic heterogeneity and rationalize targeting 14 subtype-specific metabolic vulnerabilities to advance breast cancer therapy. 15 16 17 18 RESULTS Abundance 3 To discover protein distinctions of primary human MEC populations we generated their 4 global proteomes. We performed mass spectrometry-based shotgun proteomics on 5 equivalent numbers of FACS-purified basal (CD45 -CD31 -CD49f hi EpCAM lo-med ; color-6 coded as red in all figures), luminal progenitor (CD45 -CD31 -CD49f lo EpCAM med ; light 7 blue), and mature luminal (CD45 -CD31 -CD49f hi EpCAM lo ; dark blue) cells from 10 normal 8 human breast samples obtained from reduction mammoplasties (Figure 1B, S1A). Our 9 patient cohort represented diverse physiologies, covering a wide age range (28-67 years 10 old) and sex hormone status (3 luteal, 3 follicular, 4 post-menopausal). We detected 6034 11 unique proteins ( Figure 1B). Expression of known markers for each mammary cell type 12 was accurately captured by our proteomics data (Figure S1B); higher abundance of 13 Vimentin and ITGA6 (Integrin α6, CD49f) was seen in basal cells, higher KIT and 14 ALDH1A3 levels in luminal progenitors, and higher GATA3, FOXA1 and KRT8/18 15 (Cytokeratin 8/18) in the mature luminal. Principal component analysis highlighted the 16 distinct proteomes of mammary cells; the dominant clustering feature was mammary cell 17 type with a minor segregation of post-menopausal samples within each cluster (Figure 181C). Out of the 6034 proteins, 5881 were detected in all three cell types ( Figure S1C).

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Section: Resultsmentioning

confidence: 99%

Mammary epithelial cells have lineage-restricted metabolic identities

Mahendralingam

Aliar

Casey

et al. 2019

Preprint

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“…Aneuploid cells from mice bearing a conditional knockout of Mps1 , encoding a mitotic checkpoint kinase, showed a set of significantly overexpressed genes involved in cell metabolism (Foijer et al, 2014). More recently, highly aneuploid colorectal cells were found to be sensitive to an antagonist of ceramide glucosyltransferase due to overabundance of intracellular ceramide, possibly as a result of dysregulated sphingolipid metabolism (Tang et al, 2017). It was also shown that ceramide levels were increased in some aneuploid budding yeast strains and further increasing ceramide levels either genetically or pharmacologically could slow down their proliferation (Hwang et al, 2017).…”

Section: Aneuploidy-associated Stressmentioning

confidence: 99%

Cellular Stress Associated with Aneuploidy

et al. 2018

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Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells.

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“…For example, aneuploid budding yeast have elevated levels of proteotoxic stress, presumably due to the perturbation of the required stoichiometry of protein complexes 19 . Another example is the increased sensitivity of aneuploid yeast to perturbation of sphingolipid metabolism 20,21 . Although some of these findings were successfully recapitulated in mammalian cells 21,22 , the systematic identification of aneuploidy-induced vulnerabilities remains elusive in human cancer.…”

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confidence: 99%

“…Another example is the increased sensitivity of aneuploid yeast to perturbation of sphingolipid metabolism 20,21 . Although some of these findings were successfully recapitulated in mammalian cells 21,22 , the systematic identification of aneuploidy-induced vulnerabilities remains elusive in human cancer. A major reason for that is that aneuploidy is notoriously difficult to study: it affects multiple genes at once, it plays distinct roles in different contexts, and it is hard to engineer experimentally.…”

mentioning

confidence: 99%

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

Cohen-Sharir

McFarland

Abdusamad

et al. 2020

Preprint

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Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between neardiploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.

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Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis

Cited by 43 publications

References 54 publications

Mammary epithelial cells have lineage-restricted metabolic identities

Mammary epithelial cells have lineage-restricted metabolic identities

Cellular Stress Associated with Aneuploidy

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

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