Author ORCID Identifier

https://orcid.org/0000-0003-3730-9004

Date of Graduation

8-2019

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Michael A. Davies

Committee Member

Philip Lorenzi

Committee Member

John De Groot

Committee Member

Russell Broaddus

Committee Member

Dihua Yu

Abstract

We recently showed via RNA-sequencing (RNA-seq) analysis of clinical samples that melanoma brain metastases (MBMs) have higher expression of oxidative phosphorylation (OXPHOS) genes (including PPARGC1A or PGC1α) than patient-matched extracranial metastases (ECMs). Thus, the central hypothesis of this dissertation is that OXPHOS plays a critical role in the pathogenesis of MBMs.

RNA-seq analysis identified increased expression of OXPHOS genes in intracranial (ICr) vs. subcutaneous (SQ) xenografts of 4 different human melanoma cell lines. Increased OXPHOS in the ICr xenografts was confirmed by direct metabolite analysis and [U-13C]-glucose tracing analysis. Together, these studies indicate that the brain TME mediates OXPHOS enrichment in MBMs.

The functional significance of OXPHOS in MBM pathogenesis was tested using IACS-010759, a potent OXPHOS inhibitor currently in phase I clinical trials. IACS-010759 treatment of an RCAS-TVA mouse model of spontaneous MBM and lung metastasis significantly decreased the incidence of detectable MBMs but did not affect primary tumor growth or the incidence of lung metastases. To clarify if OXPHOS promotes the formation of MBMs or the outgrowth of micrometastases, we used an imageable experimental MBM model to demonstrate that IACS-010759 treatment prevented the growth of MBMs but did not prevent their formation, and had no effect on the formation or growth of lung metastases. Likewise, knockdown of PGC1α significantly extended the survival of mice challenged by intracranial injection of melanoma cell lines but had no effect on subcutaneous tumor growth.

Hierarchical clustering analysis of surgically resected MBMs by OXPHOS genes identified subsets of MBMs particularly enriched (High-OXPHOS) and depleted (Low-OXPHOS) in OXPHOS. High-OXPHOS MBMs were characterized by mTORC1 pathway activation, immunosuppression, and enhanced glutamine metabolism. IACS-010759 treatment and treatment with the novel glutaminase inhibitor CB839 significantly improved the survival of mice bearing High-OXPHOS, MAPKi-resistant ICr xenografts.

Together these studies indicate that the brain TME mediates OXPHOS enrichment in MBMs. Further, while OXPHOS is not a critical determinant of brain metastasis formation, it plays a crucial role in intracranial tumor growth. These findings suggest that targeting this metabolic pathway and/or its dependencies may be an effective strategy for MBM treatment.

Keywords

melanoma, brain metastases, tumor metabolism, oxidative phosphorylation

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