Perturbation-Based Modeling Unveils the Autophagic Modulation of Chemosensitivity and Immunogenicity in Breast Cancer Cells
artículo original
Fecha
2021-09-18Autor
Quirós Fernández, Isaac
Figueroa Protti, Lucía
Arias Arias, Jorge Luis
Brenes Cordero, Norman
Mora Rodríguez, Javier Francisco
Mora Rodríguez, Rodrigo Antonio
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In the absence of new therapeutic strategies, chemotherapeutic drugs are the most widely
used strategy against metastatic breast cancer, in spite of eliciting multiple adverse effects and having
low responses with an average 5-year patient survival rate. Among the new therapeutic targets
that are currently in clinical trials, here, we addressed the association between the regulation of the
metabolic process of autophagy and the exposure of damage-associated molecular patterns associated
(DAMPs) to immunogenic cell death (ICD), which has not been previously studied. After validating
an mCHR-GFP tandem LC3 sensor capacity to report dynamic changes of the autophagic metabolic
flux in response to external stimuli and demonstrating that both basal autophagy levels and response
to diverse autophagy regulators fluctuate among different cell lines, we explored the interaction
between autophagy modulators and chemotherapeutic agents in regards of cytotoxicity and ICD
using three different breast cancer cell lines. Since these interactions are very complex and variable
throughout different cell lines, we designed a perturbation-based model in which we propose specific
modes of action of chemotherapeutic agents on the autophagic flux and the corresponding strategies
of modulation to enhance the response to chemotherapy. Our results point towards a promising
therapeutic potential of the metabolic regulation of autophagy to overcome chemotherapy resistance
by eliciting ICD.
External link to the item
https://doi.org/10.3390/metabo11090637Colecciones
- Microbiología [1171]