Abstract 1313: Hepatic pre-metastatic niche formation by uveal melanoma extracellular vesicles
Notice bibliographique
Résumé
Abstract Background: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and half cases develop incurable liver metastases. As the liver is the first and often the only metastatic site of UM, this suggests the existence of a favorable microenvironment for UM cells. Extracellular vesicles (EVs) are released by cancer cells, which allow oncoproteins or genetic material to be transferred to distant cells in order to modify their microenvironment and promote the spread of cancer. Our hypothesis is that EVs from the ocular tumor precondition the hepatic stroma by activating hepatic stellate cells (HSteCs) to promote the colonization by metastatic cells. Our study aims to determine the role of melanomic EVs in the mechanisms governing the remodeling of the liver microenvironment, including the stromal stiffness. Methods: EVs were isolated from UM cells and choroidal melanocytes by differential centrifugation. The mechanisms of EV internalization in HSteCs were investigated by confocal microscopy using inhibitors of endocytosis pathways. The impact of melanomic EVs on the viability, energy metabolism and gene expression profile of targeted cells was studied using MTS assay, LIVE/DEAD assay, and RNA-Sequencing. In addition, activation of the mechanotransduction signaling pathways were studied by immunofluorescence and Western blotting (FAK phosphorylation and YAP nuclear translocation. HSteCs were seeded on hydrogels of varying stiffness (0.8/2.5/8 kPa; which mimic the stiffness of healthy to highly fibrotic liver), and then exposed to EVs to study their level of activation/contractility by confocal microscopy (⍺SMA+) and traction force microscopy. The preconditioning of the liver by melanomic EVs were studied by in vivo fluorescence imaging in immunodeficient mice. The liver was collected, and the EV-driven activation of HSteCs and their remodeling of the hepatic stroma were analyzed by confocal and polarization microscopy. The number of metastatic lesions and the fibrosis were studied by histological staining using Masson's Trichrome and Hematoxylin & Eosin stains. Results: Melanomic EVs increased the proliferation and energy metabolism of HSteCs, and activated pro-fibrotic signaling pathways. The increased rigidity of hydrogels, which mimic advanced pathological stages, favored the internalization of melanomic EVs by HSteCs. The preconditioning of the liver by melanomic EVs promoted the development of metastases and the production of a stiffer extracellular matrix in the animal model. Conclusions: Melanomic EVs preconditioned the liver by establishing a pre-metastatic niche through the activation of stellate cells. A better understanding of the bidirectional crosstalk between metastatic UM cells and stellate cells at the premetastatic and micro-metastatic stages in the liver will allow to identify new molecular mechanisms or biophysical features that could be therapeutically targeted. Citation Format: Kelly Coutant, Léo Piquet, Enola Bollmann, Andrew Mitchell, François Bordeleau, Solange Landreville. Hepatic pre-metastatic niche formation by uveal melanoma extracellular vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1313.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
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 ».