Abstract A26: Identification of a novel therapeutic target in lung adenocarcinoma
Notice bibliographique
Résumé
Abstract The reactivation of biologic signaling events that occur throughout fetal development has been observed during malignant cell transformation and tumor progression. Transcription factors are typically at the hub of these signaling events, such as NKX2-1 and several ETS transcription factors. ELF3 is an uncharacterized ETS family member that is highly expressed during fetal lung development and could play a biologic role in lung cancer based on its location within the recurrently gained chromosome 1q. We hypothesize that ELF3 is a novel oncogenic transcription factor and a therapeutic target. Multiple independent datasets encompassing 1,685 clinical samples of lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), small cell lung cancer, and nonmalignant lung tissues were analyzed to establish the frequency of ELF3 overexpression and underlying genetic mechanisms of selection. ELF3 overexpression was validated by immunohistochemistry. Associations with patient survival were tested using the log-rank method. Isogenic cell lines were established to assess oncogenic phenotypes including tumor growth in a xenograft model. Protein-protein interaction (PPI) networks were constructed around ELF3, and integrated pathway analysis was performed to decipher the signaling network disruptions resulting from ELF3 overexpression. ELF3 overexpression was frequently observed in LUAD (>2-fold: BCCA 73% TCGA 40%), but was not observed in other lung cancer subtypes. Similarly, high ELF3 expression was significantly associated with poor overall survival of LUAD patients (p<0.0001), but not LUSC patients. These clinical associations prompted further examination of ELF3 in the LUAD subtype of lung cancer. ELF3 knockdown in LUAD cell lines resulted in significantly reduced proliferation, viability, and anchorage-independent growth, demonstrating that ELF3 regulates oncogenic phenotypes. Loss of ELF3 abolished the ability of LUAD cells to establish tumors in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumor growth. ELF3 overexpression is associated with remodeling of 23 direct PPI networks, resulting in loss of interaction with proteins such as NFKB1 and MYC, while forming new interactions with NKX2-1, HOXA5 and ERBB3. Pathway analysis suggests a transcriptional reprogramming from inflammatory and MAPK signallng in nonmalignant and ELF3-low tissues, to adhesion and motility pathways in transformed tissues displaying high ELF3 expression. Core pathways included cell cycle, apoptosis, WNT, and NOTCH signaling, agreeing with our cell models. While mutations in ELF3 were rare, up to 80% of LUAD patients harbored focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus, which resulted in transcript overexpression. We have deciphered the oncogenic role of ELF3 in LUAD. Its requirement for tumor growth in our model indicates that therapeutic targeting of ELF3 could benefit the 73% of patients who display ELF3 overexpression. Citation Format: Katey S.S. Enfield, Erin A. Marshall, Christine Anderson, Kevin W. Ng, Sara Rahmati, Zhaolin Xu, Calum E. MacAulay, Stephen Lam, William W. Lockwood, Raj Chari, Aly Karsan, Igor Jurisica, Wan L. Lam. Identification of a novel therapeutic target in lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A26.
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) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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 | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».