Colección INTI-SNRD


Título: Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
Fuente: PLoS ONE, 10(9)
Autor/es: Rodríguez, Cristina E.; Reidel, Sara I.; Bal de Kier Joffé, Elisa D.; Jasnis, Maria A.; Fiszman, Gabriel L.
Materias: Cáncer; Células; Medicina; Quimioterapia; Citología
Editor/Edición: PLOS; 2015
Licencia: https://creativecommons.org/licenses/by/4.0/
Afiliaciones: Rodríguez, Cristina E. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Reidel, Sara I. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; Argentina
Bal de Kier Joffé, Elisa D. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Jasnis, Maria A. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fiszman, Gabriel L. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; Argentina

Resumen: Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.
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