Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Maureen E. Murphy

Abstract

The tumor microenvironment (TME) is comprised of both transformed (cancerous) and non-transformed cells. Major non-transformed cellular components of the TME include cancer associated fibroblasts, blood and lymphatic vessels, and immune cells (such as T-lymphocytes, macrophages and dendritic cells). While these cellular components normally serve to protect the host and maintain homeostasis, cancer cells co-opt their functions to establish a microenvironment that is conducive to tumorigenesis. Interestingly, cancer cell intrinsic properties, such as oncogenic mutations and loss of tumor suppressor function have been shown to influence the TME. TP53 is a gene that encodes for the protein p53, and is the most highly mutated gene in human cancer. Recently the tumor suppressive functions of p53 have been extended to include the regulation of the immune microenvironment. Our lab has identified an African-centric polymorphism of p53 that leads to a proline-to-serine conversion at amino acid 47 (here-in S47), resulting in poor intrinsic tumor suppressive properties. S47 mice have defective ferroptosis that leads to iron accumulation, along with improved metabolic efficiency due to enhanced mTOR activity. These mice develop spontaneous tumors, and have an anti-inflammatory phenotype. We used S47 mice to investigate the importance of p53 in immune regulation of the TME. We found that S47 mice have an immunosuppressed microenvironment and respond more poorly to immune checkpoint inhibition, compared to wild type mice. In a second, unrelated area of investigation, we also wanted to determine the contribution of local microenvironments on the efficacy of anti-cancer therapy. The brain is a common site of melanoma metastasis, and melanoma brain metastases (MBMs) have been shown to interact with cellular components in the brain, including astrocytes. Astrocytes, which normally protect the brain during CNS insult, promote the survival and chemoresistance of MBMs via direct contact and paracrine signaling. However, how astrocytes affect the response of MBMs to targeted therapies, such as MAPK inhibitors, remains unknown. Here we show that astrocytes enhance the sensitivity of MBMs to MEK inhibitors via downregulation of the transcription factor ID3. We also show that ID3 can be pharmacologically targeted by HSP70 inhibition and that our novel HSP70 inhibitor synergizes with MEK inhibitors in NRAS mutant melanoma. Taken together, this work highlights the ways in which tumor interactions with components of the TME facilitate cancer cell responses to anti-cancer therapies. We hope to use this work to inform clinical approaches to personalized medicine, as well as suggest novel drug combinations for the treatment of cancer.

Embargoed

Available to all on Friday, January 31, 2025

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