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Start Over Author "Kari B. Wisinski" Journal ebiomedicine
2 results on '"Kari B. Wisinski"'

1. Organotypic microfluidic breast cancer model reveals starvation-induced spatial-temporal metabolic adaptationsResearch in context

Author

Jose M. Ayuso, Amani Gillette, Karina Lugo-Cintrón, Suehelay Acevedo-Acevedo, Ismael Gomez, Molly Morgan, Tiffany Heaster, Kari B. Wisinski, Sean P. Palecek, Melissa C. Skala, and David J. Beebe

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS, tumor cells remain inside the mammary duct, growing under a microenvironment characterized by hypoxia, nutrient starvation, and waste product accumulation; this harsh microenvironment promotes genomic instability and eventually cell invasion. However, there is a lack of biomarkers to predict what patients will transition to a more invasive tumor or how DCIS cells manage to survive in this harsh microenvironment. Methods: In this work, we have developed a microfluidic model that recapitulates the DCIS microenvironment. In the microdevice, a DCIS model cell line was grown inside a luminal mammary duct model, embedded in a 3D hydrogel with mammary fibroblasts. Cell behavior was monitored by confocal microscopy and optical metabolic imaging. Additionally, metabolite profile was studied by NMR whereas gene expression was analyzed by RT-qPCR. Findings: DCIS cell metabolism led to hypoxia and nutrient starvation; revealing an altered metabolism focused on glycolysis and other hypoxia-associated pathways. In response to this starvation and hypoxia, DCIS cells modified the expression of multiple genes, and a gradient of different metabolic phenotypes was observed across the mammary duct model. These genetic changes observed in the model were in good agreement with patient genomic profiles; identifying multiple compounds targeting the affected pathways. In this context, the hypoxia-activated prodrug tirapazamine selectively destroyed hypoxic DCIS cells. Interpretation: The results showed the capacity of the microfluidic model to mimic the DCIS structure, identifying multiple cellular adaptations to endure the hypoxia and nutrient starvation generated within the mammary duct. These findings may suggest new potential therapeutic directions to treat DCIS. In summary, given the lack of in vitro models to study DCIS, this microfluidic device holds great potential to find new DCIS predictors and therapies and translate them to the clinic. Keywords: Breast cancer, DCIS, Microfluidics, Organotypic, 3D model

Published
2018
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2. Organotypic microfluidic breast cancer model reveals starvation-induced spatial-temporal metabolic adaptations

Author

Ismael Gomez, David J. Beebe, Jose M. Ayuso, Kari B. Wisinski, Suehelay Acevedo-Acevedo, Molly M. Morgan, Tiffany M. Heaster, Melissa C. Skala, Sean P. Palecek, Karina M. Lugo-Cintrón, and Amani A. Gillette

Subjects
3D model, 0301 basic medicine, Genome instability, Research paper, DCIS, Microfluidics, Cell, Breast Neoplasms, Biology, Models, Biological, Genomic Instability, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, Breast cancer, 0302 clinical medicine, Cell Line, Tumor, Organotypic, Gene expression, Tumor Microenvironment, medicine, Humans, Neoplasm Invasiveness, skin and connective tissue diseases, Hydrogels, General Medicine, Microfluidic Analytical Techniques, Hypoxia (medical), Ductal carcinoma, Phenotype, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, chemistry, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Female, medicine.symptom, Tirapazamine
Abstract

Background Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS, tumor cells remain inside the mammary duct, growing under a microenvironment characterized by hypoxia, nutrient starvation, and waste product accumulation; this harsh microenvironment promotes genomic instability and eventually cell invasion. However, there is a lack of biomarkers to predict what patients will transition to a more invasive tumor or how DCIS cells manage to survive in this harsh microenvironment. Methods In this work, we have developed a microfluidic model that recapitulates the DCIS microenvironment. In the microdevice, a DCIS model cell line was grown inside a luminal mammary duct model, embedded in a 3D hydrogel with mammary fibroblasts. Cell behavior was monitored by confocal microscopy and optical metabolic imaging. Additionally, metabolite profile was studied by NMR whereas gene expression was analyzed by RT-qPCR. Findings DCIS cell metabolism led to hypoxia and nutrient starvation; revealing an altered metabolism focused on glycolysis and other hypoxia-associated pathways. In response to this starvation and hypoxia, DCIS cells modified the expression of multiple genes, and a gradient of different metabolic phenotypes was observed across the mammary duct model. These genetic changes observed in the model were in good agreement with patient genomic profiles; identifying multiple compounds targeting the affected pathways. In this context, the hypoxia-activated prodrug tirapazamine selectively destroyed hypoxic DCIS cells. Interpretation The results showed the capacity of the microfluidic model to mimic the DCIS structure, identifying multiple cellular adaptations to endure the hypoxia and nutrient starvation generated within the mammary duct. These findings may suggest new potential therapeutic directions to treat DCIS. In summary, given the lack of in vitro models to study DCIS, this microfluidic device holds great potential to find new DCIS predictors and therapies and translate them to the clinic., Graphical abstract Unlabelled Image

Published
2018

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