Dissertation/Thesis Abstract

Metabolic Consequences of an Aging Microenvironment in Melanoma
by Alicea, Gretchen Marie, Ph.D., University of the Sciences in Philadelphia, 2020, 110; 28000677
Abstract (Summary)

“Aged” melanoma patients (> 55 years old) have poorer prognosis and reduced response rates to targeted therapy relative to “young” patients (< 40 years old). Here, we report an altered metabolic landscape in the aged tumor microenvironment (TME) as critical for melanoma aggressiveness. Aged fibroblasts uptake high levels of glucose compared to their young counterparts, which fuels lipid production. Melanoma cells cultured in an aged TME in vitro or in vivo display elevated intracellular lipid levels and increased metastatic potential relative to melanoma cells in a young TME. Further, lipidomics reveal an elevated lipid profile (i.e., triglycerides, ceramides, and cholesterol) preferentially secreted by aged fibroblasts relative to young. In turn, we show that melanoma cells adaptively increase extracellular fatty acid scavenging via the lipid transporter FATP2 in the lipid rich aged TME. Melanoma cells cultured in the aged TME also display an increased oxygen consumption rate (OCR) relative to those grown in young TME, which could be ablated when fatty acid transport into the mitochondria is blocked with etomixir. Notably, melanoma cells in the aged TME treated with BRAFi/MEKi in combination with a FATP2 inhibitor display decreased OCR relative to BRAFi/MEKi inhibitor alone, which paralleled the increased overall survival of aged mice treated with BRAFi/MEKi/FATP2i relative to either agent alone. To rule out off-target effects of the FATP2 inhibitor, we used a doxycycline inducible system for FATP2 knockdown in melanoma cells and reproduced the abrogation of tumor growth and extension of survival in aged immune-competent mice when combined with BRAFi/MEK therapy. Additionally, elevated FATP2 levels correlate with worse response in human patients. We hypothesize the aged TME triggers adaptive metabolic plasticity of melanoma cells critical for therapy escape.

Indexing (document details)
Advisor: Weeraratnna, Ashani T.
Commitee: Keith, Brian D., Schug, Zachary, Myers, Kenneth A., Mercier, Isabelle
School: University of the Sciences in Philadelphia
Department: Cancer Biology
School Location: United States -- Pennsylvania
Source: DAI-B 81/12(E), Dissertation Abstracts International
Subjects: Biology, Molecular biology
Keywords: Aging, Melanoma, Metabolism, Microenvironmennt
Publication Number: 28000677
ISBN: 9798635295342
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