Abstract GMM-020: CELL OF ORIGIN, MUTATION AND MICROENVIRONMENT: MODELING EARLY EVENTS OF ENDOMETRIOSIS ASSOCIATED CANCERS
Notice bibliographique
Résumé
Abstract Both clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are associated with ovarian endometriotic cysts, which is believed to be their precursor lesion. However, genomic evidence is lacking which could explain how these two clinically distinct histotypes of ovarian cancer arise from the same precursor lesion. We therefore hypothesized that these cancers arise from distinct cells of origin within endometrial tissue. Global proteomic analysis of ovarian cancer histotypes identified CTH as a marker for CCOC. We further found that CTH is highly expressed in the ciliated cells of endometrium (both ectopic endometrium and endometriosis), and of the fallopian tube, with little expression in the secretory cells. We also find that other ciliated cell markers are expressed in CCOC, whereas endometrial secretory cell markers are expressed in ENOC. We propose a new model of CCOC and ENOC histogenesis wherein ENOC is derived from cells of secretory cell lineage whereas CCOC is derived from cells of ciliated cell lineage. However, it remains unclear how external factors in the endometriotic cyst cooperate with cell of origin and mutation to promote cancer formation. To study normal tissue biology, we are using organoid cultures of normal endometrium. As ciliated cells of the endometrium are rare, and we have a particular interest in determining whether they have other features that may link them to CCOC, we used a Notch inhibitor, DBZ, to force ciliated cell differentiation in the organoids. We observed a dramatic shift in the cellular content with DBZ treamtment towards ciliated cells. We performed single cell RNA sequencing (scRNAseq) on these endometrial organoids. In the normal endometrial organoids, cells were predominantly a secretory phenotype, characterized by high ESR1 expression, with a minor ciliated cell population. The ciliated cell population expressed several known ciliated markers (FOXJ1 and DNAH12). Upon treatment with DBZ, the number of secretory cells decreases dramatically and two populations of cells emerge which have ciliated cell markers. The larger ciliated cell population is similar to the ciliated cells in the untreated organoids. The smaller ciliated cell population in the DBZ treated organoids express some ciliated cell markers, but clusters separately from normal ciliated cells. We believe this population may reprepsent an intermediary population, which has not fully differentiated. Interestingly, this population expresses the cytokine IL6, while the normal ciliated cell population does not. This is of note because CCOCs express more IL6 compared to the other histotypes. Therefore, we can speculate that this intermediary ciliated cell population may represent cells from which CCOC arise, however more testing is needed. In the future, the scRNAseq data from organoids will be compared to CCOC and ENOC tumors to determine whether the tumors resemble more closely one population of normal cells. We will use viral transduction to introduce mutations into the organoid cultures to determine whether specific mutation leads to transformation towards a CCOC or ENOC-like phenotype. These studies will enable us to tease apart the relative contribution of mutation, microenvironment and the cell of origin to promote tumor formation. Citation Format: Dawn R Cochrane, Basile Tessier-Cloutier, Germain Ho, Kieran Campbell, Evan Gibbard, Katherine M Lawrence, Tayyebeh Nazeran, Anthony N. Karnezis, Clara Salamanca, Angela S Cheng, Jessica N McAlpine, Sohrab Shah, Lien N Hoang, C Blake Gilks and David G Huntsman. CELL OF ORIGIN, MUTATION AND MICROENVIRONMENT: MODELING EARLY EVENTS OF ENDOMETRIOSIS ASSOCIATED CANCERS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-020.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 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 ».