Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.