Abstract B003: Identification of novel genes that regulate aneuploidy tolerance by attenuating aneuploidy-induced stresses
Notice bibliographique
Résumé
Abstract Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is the most common genetic aberration in cancer and is associated with a worse prognosis and advanced disease. However, in non-transformed cells, aneuploidy has a substantial fitness cost, leading to cell cycle arrest and cell death. This fitness cost is the result of several cellular stresses associated with aneuploidy, including proteotoxic, metabolic, mitotic and replication stress. Therefore, for aneuploidy to become beneficial, tolerance mechanisms that enable cancer cells to cope with aneuploidy-induced cellular stresses must come into play. Such mechanisms may uncover novel synthetic lethalities of aneuploid cancer cells. To this end, we systematically dissected the cellular mechanisms that facilitate aneuploidy tolerance. We combined large-scale analyses of gene expression, as well as genetic and pharmacological dependency datasets from human tumors, cancer cell lines and non-transformed cells, to identify genes and pathways associated with aneuploidy tolerance. We identified 55 genes associated (with high confidence) with aneuploidy tolerance. Gene set enrichment analysis (GSEA) revealed an enrichment for ribosome biogenesis and translation, DNA repair, replication stress and the p53 pathway. Interestingly, these pathways were all previously implicated with the aforementioned aneuploidy-induced cellular stresses. We plan to conduct a dependency mini-screen to validate the top ‘hits’ from our comprehensive bioinformatic analysis, and to explore the role of validated candidates in conferring aneuploidy tolerance. One of the top ‘hits’ of our exploratory analysis was a novel gene with an unclear cellular function. We experimentally confirmed that this gene was over-expressed in aneuploid cells, across several isogenic systems of matched diploid-aneuploid cell lines. Aneuploidy induction using MPS1 inhibitors led to its significant upregulation, demonstrating that its increased expression is a general feature of aneuploid cells. Mechanistically, we found that the novel gene had a role in regulating chromosome segregation, as its knockdown increased the rate of mitotic aberrations – as well as the sensitivity to mitotic checkpoint inhibition – resulting in increased chromosomal instability. We now study the molecular basis for the effect of this novel gene on aneuploidy tolerance. Specifically, we knocked it down in aneuploid cells, and over-expressed it in diploid cells, and we currently explore how these manipulations affect the above-mentioned aneuploidy tolerance pathways, namely replication stress, ribosome biogenesis, DNA damage repair and tp53 activation. In summary, we revealed a novel gene that is a key regulator of aneuploidy tolerance in cancer cells, likely due to its direct involvement in pathways required for the cellular coping with aneuploidy-induced stresses. Citation Format: Yonatan Eliezer, Adi V Tarrab, Tal Ben-Yishay, Hajime Okada, Tom Winkler, Uri Ben-David. Identification of novel genes that regulate aneuploidy tolerance by attenuating aneuploidy-induced stresses [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 B003.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».