Abstract P1-13-02: The Aberrant Activity of Retrotransposon Elements Mediates the Chemo-tolerant Persister Cells Relapse in TNBC
Notice bibliographique
Résumé
Abstract The emergence of acquired drug resistance through therapeutic treatment remains a critical threat to efficient chemotherapy, target therapy, or immune therapy. These resistant cancer cells most often lead to relapse or metastasis. The development of drug resistance is a multi-step evolutionary adaptation for cancer cells. Tumor heterogeneity, cancer cells’ plasticity, and microenvironment contribute to the resistant clone’s formation. Therefore, a time-lapse adaptation model is critical to define the mechanism of drug resistance evolution. Recently, several studies have revealed that the initial acquired drug resistance might be conferred by transient events, such as drug-tolerant persisters (DTP) that might occur in a subpopulation of the cancer cells at the early stage of the treatment, which were then followed by the transcriptomic reprogramming and secondary-wave genetic mutations in the progression of resistance development. In the clinic, chemotherapy is still the mainstream treatment for TNBC, and one of the primary chemo agents is doxorubicin. Although the initial responsive rate of doxorubicin-based chemotherapy is up to 70%, it is well recognized that TNBC cells usually generate an evolutionary adaptive response that can result in the acquired drug-resistance and multi-drug resistant phenotypes. To date, numerous different mechanisms of acquired chemo-resistance have been reported, but the vast majority of these results have been derived from the continuous-high-dose-exposure acquired resistant cell line models. Since the chemo-treatment dosage in these artificial models is well above what is physiologically achievable in patients, few of them can mimic the actual situation of resistance development or improve the clinical trial outcomes. Moreover, most of these studies only characterized the terminal resistant cells, which are challenging to be resensitized because of their dominant genetic mutations. In this study, we hypothesize that the TNBC chemo-resistant cells may derive from the early-stage reversible chemo-tolerant “DTP-like” (CTP) cells, and early-stage epigenetic landscape perturbation might determine the progression of chemo-resistance development. To test the hypothesis and overcome the previous model limitations, based on the clinical drug exposure kinetics for doxorubicin, we developed an in vitro “pulsing-treatment CTPs regrowth” model (referred to as CTP model), which could mimic the clinical treatment and provide therapeutically relevant insights into the initial drug-induced stress response and resistance development. Leveraging this CTP model, we are able to define the early event for drug response, in which the doxorubicin-treated cells showed a senescence-like phenotype, and the interferon alpha (type I) pathway was activated. Furthermore, unexpectedly, we found that the expression of HERVs was significantly activated but LINE1s not. To further explore the TEs reactivation, we did the single cell RNA-seq for 0h, 2h, and 4 days samples. With a novel bioinformatic workflow, we integrated the TE expression information with coding genes mRNA profiling from the same single cell RNA-seq dataset and identified the IFN-enriched cluster had higher expression of HERVs. Herein, a subpopulation of HERVhigh cells with IFN activation was identified as a “hot-cluster” which might be the early determinant in the resistance evolution. Citation Format: Zijian Zhang, Yiyang Wang, Xinluo Luo, Xuwen Li, Xiaomei Zhan, Yumin Zheng, Jun Ding, Tao Wu. The Aberrant Activity of Retrotransposon Elements Mediates the Chemo-tolerant Persister Cells Relapse in TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-02.
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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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,003 |
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 ».