Role of IRE1-XBP1 arm in transendothelial migration of TNBC brain metastatic cells
Notice bibliographique
Résumé
Introduction: Breast cancer represents the second most frequent cause of brain metastasis. 30% of the patients suffering from Triple Negative Breast Cancer (TNBC) develop brain metastasis which confers poor prognosis to breast cancer patients. However, the mechanisms that facilitate brain metastasis are not fully understood. TNBC cells have high levels of endoplasmic reticulum (ER) stress and show activation of the IRE1 pathway of the Unfolded Protein Response (UPR). Our lab previously demonstrated that MDA-231/BR cells, the brain metastatic subline of MDA-MB-231, have high endogenous levels of IRE1 activity suggesting that UPR pathway supports cancer cell survival under ER stress. My research investigates the involvement of the UPR IRE1 arm in cell survival and transendothelial migration of MDA-231/BR. Methods: Characterization of MDA-231/BR cells under different ER stress inducers and the IRE1α RNAse inhibitor MKC8866 was performed by Western blot experiments and viability assays. shXBP1 clones were established and assessed for successful downregulation of sXBP1 by Western blot detection. Cell migration was assessed by real time cell analysis and transendothelial Boyden-chamber migration assay. Cytokines secreted from MDA-231/BR under induced ER stress and MKC8866 were determined. Brain endothelial cells were subjected to MDA-231/BR conditioned media to determine changes in cell viability and differences in gene expression of tight junctional proteinsby qPCR. Preliminary in vivo analysis was performed to assess the effect of XBP1 silencing on MDA-231/BR brain metastasis. Results: MDA-231/BR cells showed constitutive activation of the IRE1 RNase arm which wasfurther induced by serum starvation and thapsigargin. The IRE1 RNase inhibitor MKC8866 completely blocked basal and induced IRE1 RNAse activity. In contrast to serum starvation, Tg treatment activated the pro-apoptotic PERK pathway which was confirmed by reduced cell viability and increased caspase 3/7 activity. MDA-231/BR cell migration studies under treatment with MKC8866 have shown a reduction in cell migration through endothelial layers. Knockdown of XBP1 however, did not consistently reduce endothelila transmigration of MDA-231/BR cells. ER stress-induced- MDA-231/BR cells show increased secretion of pro-metastatic cytokines IL-6, VEGF-A and thrombospondin-1. Brain endothelial cells exposed to MDA-231/BR conditioned media showed increased expression of tight junctional protein occludin under IRE1 RNase inhibition. In vivo data showed no significant difference in survival of mice in control versus doxycycline treated group. Conclusion: This study showed that the study of ER stress is dependent on different types of stressors used. Induction of ER stress leads to secretion of pro-inflammatory cytokines which can indirectly affect the endothelial cells to become more permeable and allow migration of breast cancer cells.
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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 | 0,000 | 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) | 0,000 | 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 ».