Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

Abstract

Running title: Regulation of fatty acid oxidation during breast cancer metastasis Keywords: breast cancer metastasis, metabolic regulation, AKR1B10, fatty acid oxidation, lung metastasis Abstract The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10 High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10 Highenhanced metastatic colonisation with no impact on AKR1B10 Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.A defining characteristic of primary tumour cells is an ability to alter their metabolism, which provides the energy and metabolites required to sustain survival in nutrient and oxygen limiting conditions. In disseminating tumour cells this need for an altered metabolism becomes more acute, as cells have to avoid anoikis-mediated cell death in the circulation and face the challenge of surviving at the metastatic site before establishment of a productive metastatic colony. Moreover, different metastatic sites pose distinct metabolic challenges to the tumour cell 1,2 . In breast cancers, these altered metabolic dependencies are now being defined but the molecular mechanisms regulating this metabolic adaptability have yet to be identified.Here we report the analysis of a syngeneic in vivo RNAi screen to identify putative metastasis enhancers. Among the top hits from the screen was the aldo-keto

Glioma cells survival depends both on fatty acid oxidation and on functional carnitine transport by SLC22A5

“…A growing number of reports confirm that cancer cells are dependent on lipid oxidation for their survival and proliferation. In the case of breast cancer, the transition in metabolism from glucose to fatty acids was, however, detected in metastatic secondary sites, a process dependent on aldo‐keto reductase AKR1B10; it was also proposed that this metabolic change is necessary for successful colonization in metabolically changed environment (van Wevervijk et al, 2019). As far as glioblastoma multiforme is concerned, extra‐cranial metastases are rare (Beauchesne, 2011; Lun, Lok, Gautam, Wu, & Wong, 2011) because of short survival of the patients.…”

Enhanced fatty acid oxidation mediated by CPT1C promotes gastric cancer progression

“…Enhanced fatty acid oxidation mediated by CPT1C promotes gastric cancer progression (4)(5)(6)(7)(8). Cancer cells always showed high rate of fatty acid oxidation (FAO) to produce energy and thus maintaining the rapid growth of cancer cells (9)(10)(11)(12)(13). Several enzymes catalyzing FAO have been identified in solid tumors.…”

Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics

“…7). There is growing interest in the role of fatty acid metabolism in cancer progression and metastasis, 75 but little is known about its role in platinum drug efficacy and resistance. Increased levels of fatty acid oxidation have been linked to apoptosis.…”