Abstract 1198: Neuropilin-1 blockade chemosensitizes pancreatic cancer cells via dual inhibition of epithelial-mesenchymal transition and autophagy
Notice bibliographique
Résumé
Abstract Introduction: Fibrotic and malignant pancreatic ductal adenocarcinoma (PDAC) tumors are often resistant to chemotherapy, and remain a leading cause of morbidity and mortality. Epithelial–mesenchymal transition (EMT), a process by which epithelial cells lose their cell polarity and adhesion to become migratory and invasive mesenchymal stem cells, contributes to chemoresistance in PDAC. Likewise, PDAC tumors benefit from autophagy, a self-degradation pathway that confers a survival benefit against metabolic stress. Over-activation of EMT and autophagy has been linked to increased drug resistance in PDAC. Both these processes are largely mediated by TGFβ1. Recently, we demonstrated the role of neuropilin-1 (NRP-1) in TGFβ1-dependent endothelial-mesenchymal transition and fibrosis in PDAC. However, the potential mechanisms linking NRP-1 with EMT and autophagy-mediated chemoresistance remain unexplored. We hypothesized that NRP-1 blockade will enhance chemotherapeutic effect, by suppressing EMT and autophagy in PDAC. Methods: Human PDAC cells (BxPC-3) or serially gemcitabine exposed chemoresistant (CR-BxPC-3) cells were transfected with siNRP-1 or scramble using DharmaFECT-2. For EMT and chemotherapy studies, transfected cells were treated with TGFβ1 (5ng/mL, 24h), followed by gemcitabine (1μM) for 48h. RNA (24h) and protein (48h) was isolated using TRIzolTM and RIPA, respectively. EMT markers were evaluated by RT-PCR and immunoblotting/immunostaining. For autophagy studies, cells were serum starved post NRP-1 silencing and protein was isolated. For autophagy inhibition, cells were treated with bafilomycin-A1 (100nM) for 24h post NRP-1 silencing and protein was isolated. Autophagy flux (LC3-II/I) and P62 were measured by immunoblotting/immunostaining. Cell viability was evaluated by MTT assay. Results: SiNRP-1 treatment in BxPC-3 and CR-BxPC-3 cells resulted in NRP-1 knockdown and promoted cell-death after chemotherapy. TGFβ1-stimulated BxPC-3 cells demonstrated a morphological change consistent with EMT that was revoked by siNRP-1. Also, siNRP-1 maintained epithelial cellular morphology via gain of epithelial and loss of mesenchymal markers. Remarkably, CR-BxPC-3 cells exhibited enhanced EMT features. SiNRP-1 inhibited EMT and promoted cell-death by overcoming gemcitabine resistance in CR-BxPC-3 cells, possibly through reduced ERK signaling. Moreover, siNRP-1 inhibited autophagy (decreased LC3-II/I ratio and increased P62 levels) following starvation or chemotherapy stress, and enhanced cell-death after chemotherapy and autophagy inhibition in BxPC-3 cells. Conclusions: Our findings define a previously undetermined role of NRP-1 in regulating autophagy and TGFβ1-induced EMT in PDAC, suggesting that NRP-1 may represent a novel therapeutic target to overcome chemoresistance through reduced EMT and autophagy. Citation Format: Pratiek N. Matkar, Krishna K. Singh, Gerald Prud’homme, David Hedley, Howard Leong-Poi. Neuropilin-1 blockade chemosensitizes pancreatic cancer cells via dual inhibition of epithelial-mesenchymal transition and autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1198. doi:10.1158/1538-7445.AM2017-1198
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) | 0,003 | 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 ».