Abstract B15: Investigating the contribution of mTORC1-dependent stromal signaling to cancer onset in Li-Fraumeni syndrome
Notice bibliographique
Résumé
Abstract In this study, we are investigating the role of stromal mTORC1 signaling in the development of malignancy in individuals with Li-Fraumeni syndrome (LFS). LFS is a cancer predisposition syndrome that is associated with germline mutations in TP53. Individuals with LFS are faced with a significant lifetime risk of developing a wide spectrum of early-onset malignancies, thus necessitating the identification of pharmacologic agents to prevent tumor onset. Inhibitors of the mTORC1 pathway, namely rapamycin and metformin, have been shown to promote lifespan extension and delay or even prevent tumor onset in LFS mouse models. These findings are unsurprising—since wild-type p53 inhibits mTORC1—yet noteworthy, since they suggest that mTORC1 signaling plays a central role in favoring tumorigenesis in LFS. mTORC1 signaling has been implicated in promoting the protumorigenic senescence-associated secretory phenotype (SASP). The SASP constitutes the release of soluble factors, such as cytokines, growth factors, and proteases from senescent cells into the microenvironment, thus promoting oncogenesis in a paracrine manner. Interestingly, an increased incidence of senescence has been reported in LFS patients, and mutant p53 has been shown to promote the secretion of a quantitatively and qualitatively more protumorigenic SASP. As such, we believe that mTORC1 signaling in LFS stromal cells favors the production and secretion of protumorigenic factors, which may induce changes in the surrounding tissue to promote development of a precancerous niche, thus favoring tumorigenesis. Our objectives are 1) to investigate the contribution of stromal cells and stromal secreted factors in favoring tumorigenesis in LFS, and 2) to investigate the role of mTORC1 signaling in favoring these altered stromal phenotypes. To address these objectives, we co-injected patient-derived LFS fibroblasts with tumor cells of a common LFS subtype (rhabdomyosarcoma [RMS]) into immunocompromised mice and observed that tumors formed from the co-injection of RMS cells with LFS fibroblasts grew to be larger than tumors formed from co-injection with non-LFS fibroblasts. To determine whether LFS fibroblasts secrete more protumorigenic cytokines than non-LFS fibroblasts, we performed protein arrays with conditioned media (CM) from fibroblast cultures and saw that LFS fibroblasts secrete markedly higher levels of protumorigenic, SASP-related cytokines. To investigate the protumorigenic effects of fibroblast secreted factors, we treated spheroids formed from tumor cells of a common LFS subtype (osteosarcoma) with CM from LFS and non-LFS fibroblast cultures. LFS fibroblast CM had a robust proproliferative effect on spheroids, while non-LFS fibroblast CM inhibited spheroid growth. Thus far, we have observed that LFS stromal constituents favor tumor cell proliferation in vitro and in vivo, and based on the current literature, we believe that mTORC1 signaling plays a role in favoring these processes. Citation Format: Camilla M. Giovino, Nish Patel, Sangeetha Paramathas, David Malkin, Ran Kafri. Investigating the contribution of mTORC1-dependent stromal signaling to cancer onset in Li-Fraumeni syndrome [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B15.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,002 |
| 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) | 0,000 | 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 tête enseignante, 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 ».