Abstract PR008: Targeting mechanisms of dosage compensation to selectively kill aneuploid cancer cells
Bibliographic record
Abstract
Abstract Aneuploidy is an abnormal chromosome composition and a general hallmark of human cancer. Aneuploidy causes detrimental cellular stresses, but cancer cells evolve to cope with these stresses. Consequently, targeting such mitigation mechanisms is a promising potential therapeutic strategy. As an abnormal dosage of gene products from altered chromosomes can cause RNA and proteotoxic stress, dosage compensation (DC) of imbalanced gene products was reported to mitigate these stresses in aneuploid cells. However, the mechanisms that regulate DC remain elusive. To address these mechanisms, we focused on the role(s) of stress granules (SGs) and RNA binding proteins (RBPs) in aneuploid cancer cells. Our recent study revealed that aneuploid cancer cells preferentially depend on RNA and protein metabolism, and need to attenuate translation in order to cope with proteotoxic stress (Ippolito & Zerbib et al. bioRxiv 2023). In yeast, it has been previously reported that Ssd1, one of the RBPs localized in P-bodies, is indispensable to tolerating aneuploidy stress. Based on these findings, we set out to explore SGs as potential regulators of gene expression in aneuploid cancer cells. As expected, we revealed that SGs emerged in cells under acute aneuploidy stress induced by chromosome mis-segregation. These results imply that SGs are formed in cells during and right after aneuploidization, potentially as a way to mediate DC and ameliorate aneuploidy-induced cellular stress. To gain further insight into RNA regulation in aneuploid cells, we analyzed the essentiality of RBPs across cancer cell lines. We found that the RNA-editing enzyme ADAR, a suppressor of SG formation, is preferentially essential in aneuploid cancer cells. Remarkably, ADAR disruption synergized with acute aneuploidy stress to induce SGs, and ADAR exhibited increased RNA editing activity following chromosome mis-segregation. Our results suggest that SGs and their suppressor ADAR might contribute to ameliorating acute aneuploidy-induced stress. We are currently investigating the target RNAs regulated by SGs and ADAR and examining their functional role(s) in DC, with the goal of uncovering potential synthetic lethalities associated with aneuploidy in cancer cells. Citation Format: Hajime Okada, Eran Sdeor, Miriam Karmon, Erez Levanon, Uri Ben-David. Targeting mechanisms of dosage compensation to selectively kill aneuploid cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR008.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".