Abstract A058: Primary cancer-associated fibroblasts alter tumor organoid chemosensitivity through epigenetic regulation
Notice bibliographique
Résumé
Abstract Pancreatic adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in Canada with a 5-year survival rate at ∼12%. A major cause of this poor survival rate is the inefficiency of current treatments. Only 20% of patients are eligible for surgical resection while the other 80% are treated with chemotherapies (nab-paclitaxel, Gemcitabine, FOLFIRINOX) having limited efficacy. This resistance is due to the PDAC tumour microenvironment (TME), including cancer-associated fibroblasts (CAFs). Numerous studies show CAFs and the TME affect tumour growth, chemoresistance and metastasis, but the mechanisms underlying the effects are unknown. Epigenetic mechanisms, including DNA methylation and histone modifications, link environmental factors to altered gene expression. Genes encoding epigenetic mediators are often mutated or over-expressed in PDAC, but a role in resistance has yet to be defined. We hypothesize that epigenetic reprogramming occurs in pancreatic cancer cells in response to secreted factors from CAFs leading to increased therapy resistance. Methods: Most work to date on PDAC resistance has been performed with immortalized cell lines and in two dimensions. Therefore, to test our hypothesis, we established patient-derived organoids (PDO) and CAFs obtained from endoscopic ultrasound (EUS). Clinical data was obtained through the DERIVE (Determination of Response to Therapy in Individual Patients) database. To examine the effects of CAFs on PDOs, we obtained conditioned media (CM) from four, early passage CAFs, grown 48 hours in culture. Organoid media was supplemented 1:1 with CAF-CM and six PDOs grown in this media for up to 14 days. PDO growth and the response to gemcitabine, FOLFIRINOX or radiation was monitored using an Incucyte system. To identify changes in the epigenome and how this reflects changes in gene expression, DNA methylation arrays and ATAC-Seq was performed before and after treatment with CAF-CM and aligned to RNA-seq analysis on RNA isolated at the same time point. Results: Exposure of PDOs to CAF-CM resulted in altered phenotypes and molecular profiles of PDOs in a patient-specific fashion. Increased resistance to chemotherapy (Gemcitabine) and radiotherapy was observed in multiple PDOs. Changes in DNA methylation and chromatin accessibility was aligned with transcriptomic data and identified known and novel pathways linked to chemoresistance. Metabolomic and cytokine analysis on CAFs-CM identified differential enrichment of metabolites linked to epigenetic mediators. We are currently determining if these factors secreted by the CAFs promote chemo and radio-resistance. Conclusions: This study shows the importance in integrating TME components when examining novel therapeutic options. In addition, we show (1) CAFs secrete factors that enhance therapeutic resistance in PDOs and (2) these changes likely involve altered epigenetic reprogramming. Future experiments will identify the epigenetic factors that can be targeted to counteract chemoresistance. Citation Format: Emilie Jaune-Pons, Zachary Klassen, Joana Ribeiro Pinto, Maria Nica, Nadeem Hussain, Michael Sey, Ken Leslie, Matthew Cecchini, Crystal Engelage, Danielle Porplycia, Stephen Welch, Brian Yan, Christopher Pin. Primary cancer-associated fibroblasts alter tumor organoid chemosensitivity through epigenetic regulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A058.
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) | 0,004 | 0,001 |
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 ».