Abstract P6-14-07: Genetic ablation of ACF7, a member of the +TIP family of microtubule-binding proteins, impairs metastasis of HER2-positive breast cancer
Notice bibliographique
Résumé
Abstract Breast cancer is the leading cause of cancer death in women worldwide. Among the different subtypes of this disease, HER2-positive breast cancer is known to be one of the most aggressive and is linked to poor prognosis. This subtype is prone to develop metastases, reflecting a significant cellular plasticity. While the molecular machinery controlling actin dynamics is well implicated in cell invasion, the contribution of the microtubules is ill-defined. We recently conducted a functional screen to identify such regulators, and characterized ACF7, a microtubule plus-end binding protein (+TIP), as a new promoter of invasion. Here, we aim to determine the in vivo contribution of ACF7 to tumor progression and to reveal the cellular and molecular mechanisms allowing this +TIP to promote metastasis. We analyzed the expression of ACF7 at the protein level across a panel of tumor microarrays and found that it is detectable in all breast cancer subtypes with the highest levels seen in HER2-positive. To study the role of ACF7 during tumor progression, we generated an ACF7 genetically engineered mouse model of breast cancer. We exploited a HER2-positive breast cancer mouse model (MMTV-NIC) that we bred with ACF7Flox mice. This approach allows for conditional deletion of ACF7 in mammary glands and represents a powerful model to define the roles of ACF7 in HER2-driven breast cancer. Our results show that ACF7 is not involved in tumor initiation and tumor growth as no difference between number of nodules per mouse, tumor mass or number of mammary intraepithelial neoplastic lesions was shown. However, our results show a significant decrease in lung metastasis in the ACF7cKO mice. To gain mechanistic insights into the roles of ACF7 in this specific process, we derived primary cell lines from tumors isolated from MMTV-NIC-ACF7WT and MMTV-NIC-ACF7cKO mice. We explored if ACF7 contributes to migration and invasion in a HER2 context. By using live-cell imaging, we demonstrated that ACF7-null cells display defects in both random and directed cell migration, as they show a delay in wound closure. We determined that ACF7KO cells show an increase in focal adhesions size, and exhibit defects in reorienting their actin and microtubules cytoskeletons parallel to the direction of migration. ACF7 was also found to promote cell invasion since ACF7KO cells were less efficient to cross a Matrigel membrane. To investigate the metastatic potential of ACF7-null tumors, we performed RNA-sequencing using RNA isolated from MMTV-NIC-ACF7WT and MMTV-NIC-ACF7cKO tumors. We identified a striking change in expression of genes involved in epithelial to mesenchymal transition (EMT), such as for example E-cadherin, Vimentin or the transcription factor Twist. These results suggest that ACF7 promotes metastasis through maintaining an EMT state in HER2 breast cancer cells. Collectively, our work demonstrates ACF7 as an important player in HER2 positive breast cancer progression via its functions in both cell migration and cell invasion. This works also suggests that developing approaches to therapeutically target regulators of microtubule dynamics may reveal new opportunities to decrease tumor progression and metastatic expansion. Citation Format: Rebecca Cusseddu, Jean-François Côté. Genetic ablation of ACF7, a member of the +TIP family of microtubule-binding proteins, impairs metastasis of HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-07.
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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 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».