Abstract B072: Pharmacological depletion of fibrinogen suppresses the growth of primary tumors and liver metastasis of pancreatic cancer
Notice bibliographique
Résumé
Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is a highly metastatic disease often linked to the dysregulated activation of both coagulation and fibrinolytic systems. Clinically, patients show elevated plasma fibrinogen levels, particularly in those with distant metastasis. The presence of systemic fibrinogen plays a crucial role in shaping the complex tumor microenvironment (TME) characteristic of PDAC, evidenced by the excessive deposition of its active substrate, fibrin, in PDAC tumors. To investigate its contribution to disease progression, fibrinogen (Fib) was depleted from the TME in three PDAC mouse models, and the impact on tumor growth and metastasis was followed. In an aggressive, metastatic orthotopic Pa03C model, Fib depletion using antisense oligonucleotide (ASO) treatment markedly decreased the size of primary pancreatic tumors and subsequent spontaneous metastasis to the liver. Following implantation of tumor chunks from two different patients (PDX21 and PDX33), Fib depletion significantly diminished growth of primary orthotopic tumors significantly compared to control. This confirms that Fib deposition within the TME is an important driver of disease progression. Mechanistically, global proteomics revealed a remarkable upregulation of matrisome and extracellular matrix (ECM)-associated proteins, indicating that the reduction in primary orthotopic Pa03C tumors was associated with fibrin-mediated TME remodeling. Loss of fibrin matrices led to enhanced collagen, laminin, fibronectin and emilin-1 deposition, and increased presence of collagen-producing αSMA+ myofibroblasts. Spatial transcriptomics of these tumors supported this data and demonstrates an increased presence of stromal cells within the tumors from Fib-depleted mice. Notably, our data shows that fibrinogen depletion altered the ECM composition, inducing TME remodeling which led to stiffer tumors that are less metastatic. To further interrogate the role of Fib in mediating metastasis, an experimental metastasis model using intrasplenic injection of tumor cells to colonize the liver was used. In this additional model, Fib depletion did not impede the colonization of tumor cells within the liver, suggesting that Fib remodels the TME within the primary tumor which results in less tumor cells in the liver and is likely involved in one of the earlier steps of metastasis. Our data showed that pharmacologically reducing systemic fibrinogen levels impeded tumor growth and liver metastasis by preventing the formation of fibrin clots within the tumor macroenvironment which led to remodeling of the tumor and the TME. Additionally, Fib facilitates interactions between tumor cells and the extracellular matrix, promoting tumor cell survival and spread. By depleting fibrinogen, these interactions were disrupted, limiting the ability of the tumor to grow and metastasize. Our findings suggest a new avenue for clinical translation- integrating inhibitors targeting fibrinogen into chemotherapy regimens to cumulatively control the spread of pancreatic cancer. Citation Format: Nayela N Chowdhury, Dana K Mitchell, Kadri Kangro, Kierra Eldridge, Sara Abrahams, Francesca Ferraresso, Lih J Juang, Silpa Gampala, Kylee Brewster, Alexey Revenko, Christian Kastrup, Paul R Territo, D Wade Clapp, Jorge A Belgodere, Bumsoo Han, Alisa S Wolberg, Chi Zhang, Matthew J Flick, Melissa L Fishel. Pharmacological depletion of fibrinogen suppresses the growth of primary tumors and liver metastasis of pancreatic cancer [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 B072.
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) | 0,002 | 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 ».