GSBS Dissertations and Theses

ORCID ID

0000-0001-9387-6068

Publication Date

2018-10-25

Document Type

Doctoral Dissertation

Academic Program

Cell Biology

Department

Program in Systems Biology

First Thesis Advisor

Michael Lee

Keywords

cancer, Triple Negative Breast Cancer, TNBC, microenvironment, fibroblast

Abstract

Tumor heterogeneity observed between patients has made it challenging to develop universal or broadly effective cancer therapies. Therefore, an ever-growing movement within cancer research aims to tailor cancer therapies to individual patients or specific tumor subtypes. Tumor stratification is generally dictated by the genomic mutation status of the tumor cells themselves. Importantly, non-genetic influences – such as interactions between tumor cells and other components of the tumor microenvironment – have largely been ignored. Therefore, in an effort to increase treatment predictability and efficacy, we investigated how tumor-stroma interactions contribute to drug sensitivity and drug resistance.

I designed a high throughput co-culture screening platform to measure how tumor-stroma interactions alter drug mediated cell death. I identified tumor-stroma interactions that strongly desensitize or sensitize cancer cells to various drug treatments. The directionality of these observed phenotypes was dependent on the stromal cell tissue of origin. Further study revealed that interactions between tumor cells and fibroblasts modulate apoptotic priming in tumor cells to mediate sensitivity to chemotherapeutics. The principles uncovered in this study have important implications on the use of drugs that are designed to enhance apoptosis. For example, based on our screening data, I hypothesized and experimentally validated that the effectiveness of BH3 mimetic compounds would be strongly dependent on the fibroblast growth environment. Taken together, our study highlights the importance of understanding how environmental interactions alter the drug responses of cancer cells and reveals a mechanism by which stromal cells drive broad spectrum changes in tumor cell sensitivities to common chemotherapeutics.

DOI

10.13028/rx10-jp17

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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