“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.
|Advisor:||Weeraratnna, Ashani T.|
|Commitee:||Keith, Brian D., Schug, Zachary, Myers, Kenneth A., Mercier, Isabelle|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/12(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology|
|Keywords:||Aging, Melanoma, Metabolism, Microenvironmennt|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be