Abstract A031: Proteogenomic analysis of the PDAC epithelium reveals tissue markers of subtype identity and biology
Notice bibliographique
Résumé
Abstract Effective treatments for Pancreatic ductal adenocarcinoma (PDAC) remain an urgent need. Integration of molecular PDAC subtypes into clinical trials could enable translational insights into how we might refine existing and emerging therapies to improve treatment options, yet this requires robust clinically suitable marker genes and a better understanding of subtype-related biology. Here, we deeply profiled the molecular composition of human PDAC epithelia and assessed differentially expressed genes for their ability to discriminate between subtypes and mirror their key biological traits. Using well-annotated resected & advanced biospecimens, we mapped the stromal and epithelial landscapes of PDAC subtypes by combining compartment-specific transcriptomics and proteomics with quantitative image analysis of a 42-marker IHC panel and single cell RNA sequencing analyses. The integrated profiling yielded a shortlist of 30 genes that were differentially expressed at both transcriptomic and proteomic levels, and across primary and metastatic sites. These were then scrutinized for their suitability as potential single gene subtype markers through association with subtype-related epithelial and stromal biology and clinical outcomes, and via practical considerations such as immunohistochemical staining quality and cell type-specific expression patterns. Since PDAC subtypes frequently co-occur intratumorally, we furthermore assessed complementarity of different subtype marker combinations and tested association of individual markers with regional subtype biology. Annexin A8 emerged as strong IHC-suitable marker gene of the basal/squamous subtype, that exhibited prognostic and predictive value. Concordantly, Annexin A8 expression was highly correlated with TP63, a master transcription factor for the squamous subtype, and CK5, a well-established basal cell marker. In tissue stains and single cell RNAseq data, Annexin A8 specifically marked malignant epithelia but was absent from adjacent normal acini and stroma cell populations. Annexin A8 expression in PDAC epithelia was spatially distinct from the known classical subtype biomarker GATA6, as well as Claudin 18, which was the top classical/pancreatic progenitor marker gene in our integrated multiOMIC analysis. Furthermore, Annexin A8high tumors as well as Annexin A8high intratumoral regions both recapitulated key biological traits of the basal-like/squamous PDAC subtype, such as increased EMT marker expression, proliferation, hypoxia, macrophage attraction and T cell repulsion. In conclusion, integrated proteogenomic characterization of PDAC subtypes and their tissue features uncovers complementary subtype marker pairs with clinical potential and provides insights into subtype-specific biology with implications in the development of future therapeutic approaches tailored to each PDAC subtype. Citation Format: Barbara T. Grünwald, Foram Vyas, Michael Geuenich, Nathan Chan, Ricardo Gonzalez, Kazeera Aliar, Niklas Krebs, Antoine Devisme, Geoffroy Andrieux, Gun Ho Jang, Grainne O'Kane, Julie Wilson, Jennifer Knox, Faiyaz Notta, Kieran Campbell, Steven Gallinger, Melanie Boerries, Sandra Fischer, Thomas Kislinger, Rama Khokha. Proteogenomic analysis of the PDAC epithelium reveals tissue markers of subtype identity and biology [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A031.
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 | 0,001 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».