Abstract C012: Dissemination of retrotransposable elements from the non-coding genome in tumor-derived extracellular vesicles target stromal and immune cells to induce local and systemic inflammation
Notice bibliographique
Résumé
Abstract The majority of the human genome (>70%) contains non-coding DNA consisting of retrotransposable elements (RTE), such as LINE-1, SINE/Alu elements, human endogenous retroviruses (HERV), and satellite repeat DNA (Hsat2 and Hsat3). The expression of these elements is suppressed in normal adult tissues but are abnormally expressed in many cancers. Another key mechanism in cancer initiation and progression is the release of tumor-derived extracellular vesicles (EV) that are long-distance communication vehicles propagating signals from tumors inducing metabolic changes, immune dysregulation and promoting metastases across the body. Our work has uncovered a link between RTE, HERV and Hsat expression in cancer and EV in driving tumor progression and immune dysregulation. W hole transcriptome sequencing of EV derived from several different cancer cell lines and patient samples, including Ewing sarcoma, osteosarcoma, prostate, pancreatic, and breast cancer found that RTE, HERV and Hsat2,3 transcripts are highly enriched in EV versus coding region transcripts and in much higher abundance than in the tumor cell themselves. Tumor-derived EV contained dsRNA, dsDNA and RNA:DNA hybrids from these non-coding regions. Plasma EV isolated from both metastatic and non-metastatic patients also showed an enrichment of these RTE, HERV and Hsat2,3 elements and clearly differentiated healthy, normal donor EV that had little or no detectable signal. Evidence of local dissemination of these non-coding elements in EV was also found in vivo in tumor xenografts that showed transfer of Hsat2,3 transcripts into the murine stroma that naturally lack these satellite repeats. Treatment of fibroblasts and myeloid cells with tumor-derived EV triggered innate immune responses via type I IFN and pro-inflammatory cytokines, including IL-1beta, IL-6, IL-8, and TNFalpha owing to the pathogen-like nucleic acid sequences (viral mimicry) of these elements. These EV-induced chronic inflammatory effects were mainly induced through the cGAS-STING nucleic acid sensing pathway. Evidence of DNA damage in stromal fibroblasts and induced senescence was also found as a result of EV treatment. A key element of RTE is the expression of LINE-1 and HERV derived reverse transcriptase (RT) that propagates the action of RTE via RNA:DNA hybrids, dsDNA and retrotransposition in the genome. In a spontaneous estradiol-driven breast cancer model in ACI rats, long-term treatment with an HIV RT inhibitor (lamivudine/3TC) inhibited breast tumor development associated with reduced RTE activation in the mammary gland and in circulating immune cells as well as reduced chronic systemic innate inflammation. Our results suggest that RTE, HERV and Hsat activation, together with their local and systemic dissemination in EV plays an important role in cancer initiation and progression associated with chronic inflammation. We also suggest that abnormal dissemination of these activated non-coding elements in EV may also play a role in "inflammaging" facilitating not only cancer but also other chronic diseases. Citation Format: Laszlo Radvanyi, Valentina Evdokimova, Peter Ruzanov, Zhenbo Zhang, Poul Sorenson, Hendrik Gassmann, Stefan Burdach, Lincoln D. Stein. Dissemination of retrotransposable elements from the non-coding genome in tumor-derived extracellular vesicles target stromal and immune cells to induce local and systemic inflammation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C012.
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) | 0,000 | 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 | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 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 ».