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Dissertation
Investigating astrocyte reactivity in melanoma brain metastasis
Doctor of Philosophy (Ph.D.), Drexel University
Jan 2025
DOI:
https://doi.org/10.17918/00010942
Abstract
Melanoma Brain Metastases (MBM) pose a major challenge for treating metastatic melanoma. Up to 60% of advanced melanoma patients develop brain metastases, resulting in significant morbidity and mortality. MBM are often refractory due to difficulties in targeting therapeutic agents to the CNS and an attenuated immune response compared to extracranial tumors. Growing evidence suggests brain-colonizing melanoma cells grow through complex mechanisms determined by microenvironmental rather than genetic cues. Therefore, it is critical to decipher the influence of the brain microenvironment on tumor biology. Astrocytes sense changes in the brain microenvironment and regulate adaptive homeostatic responses. Their response to injury, termed reactive astrocytosis, is a process defined by changes in gene expression, signaling, growth factor secretion, and inflammatory cytokine production. Moreover, distinct reactive-substates have been described and implicated in many neurological diseases. Reactive astrocytes surround and infiltrate brain metastases, but the profile and role of reactivity is not fully understood. We hypothesize that astrocytes facilitate a pro-metastatic microenvironment that drives brain metastasis. For our studies we developed a brain adapted mouse melanoma line, D4M3a BrJ, and presently describe the dynamic impact of tumor growth on astrocyte reactivity in vivo. We demonstrate that secreted factors derived from reactive astrocytes drive melanoma growth and further identify astrocytic STAT3 signaling as a primary driver of this phenotype. Moreover, we identify a FAK/AKT signaling axis as a selective mediator of melanoma growth in brain-adapted cells and demonstrate that pharmacological inhibition of FAK attenuates growth mediated by STAT3+ astrocytes. Together, these results reveal a novel mechanism through which STAT3+ astrocytes mediate melanoma progression in the brain.
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Details
- Title
- Investigating astrocyte reactivity in melanoma brain metastasis
- Creators
- Julia K. Farnan
- Contributors
- Joshua G. Jackson (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 185 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022053037004721