Abstract PR09: Pancreatic cancer cachexia is mediated by tumor-derived PTHrP
Notice bibliographique
Résumé
Abstract Purpose: Our prior work has established that metastasis is initiated by PTHrP-driven mechanisms in PDAC. PTHLH (the gene encoding the PTHrP protein) is directly adjacent to and co-amplified along with KRAS, and this amplicon is a marker of squamous/quasi-mesenchymal/basal-like PDAC subtypes. Thus, PTHrP marks highly aggressive subsets of PDAC patients. We have generated KPCY-PthlhLoxP (herein KPCY-PthrpcKO) mice and observed a near doubling of overall survival relative to KPCY controls. Intriguingly, recent evidence has emerged for PTHrP’s role in cachexia-associated adipose tissue wasting and we posit that the dramatic survival extension in KPCY-PthrpcKO mice may be due to reduced cachexia. Results: In PDAC patients, PTHrP is co-amplified along with KRAS and correlates with significantly decreased overall survival. We generated KPCY-PthrpcKO mice and showed that they have reduced tumor burden and dramatically increased overall survival relative to KPCY controls. In parallel experiments, we treated mice with an anti-PTHrP neutralizing monoclonal antibody, which similarly reduced tumor growth and extended survival. Upon further analysis, we observed that the overall body condition of KPCY-PthrpcKO mice (and anti-PTHrP treated KPCY mice) was greatly improved, with less loss of adipose and muscle tissue. Mechanistic studies revealed that tumor cell-derived PTHrP signaling to adipocytes in white adipose tissue depots mediates cachexia. Specifically, we found that adipose tissue wasting and lipolysis were greatly reduced upon deletion or pharmacological inhibition of PTHrP. In the same vein, we uncovered that PTHrP is driving an adipocyte “browning” process, a phenomenon where energy-storing white adipocytes transdifferentiate into an energy-expending brown adipocyte-like state (often referred to as “beige” adipocytes). Preliminary results indicate direct tumor cell-adipocyte crosstalk with tumor cell secreted PTHrP binding to its cognate receptor, PTH1R, on adipocytes and activating a thermogenic (heat generating) gene program, likely through a PTH1R-PKA-CREB1 signaling axis. We additionally found that muscle wasting was reduced in KPCY-PthrpcKO mice and anti-PTHrP neutralizing antibody treated KPCY mice. Thus, genetic deletion and pharmacological inhibition of PTHrP in vivo led to a profound reduction in cachexia-related adipose tissue wasting and muscle atrophy. Re-introduction of PTHrP into a PDAC cell line with low cachexia-inducing potential (and low baseline PTHrP) dramatically increased the degree of cachexia observed upon orthotopic implantation. Additionally, mice implanted with PTHrP overexpressing tumor cells had a reduction in overall survival along with decreased overall body condition. Therefore, PTHrP is both necessary and sufficient to induce cachexia. Conclusions: This work has demonstrated the importance of the previously unappreciated roles of PTHrP signaling in driving pancreatic cancer cachexia and adipose tissue browning, and future studies will look to translate anti-PTHrP therapy into clinical trials. Citation Format: Yamini Ogoti, Jessica Peura, Calvin Johnson, Ekaterina Korobkina, Maximilian Wengyn, Robert J. Norgard, Richard Kremer, David A. Guertin, Jason R. Pitarresi. Pancreatic cancer cachexia is mediated by tumor-derived PTHrP [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR09.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| 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 ».