Blocking Lipid Synthesis Overcomes Tumor Regrowth and Metastasis after Antiangiogenic Therapy Withdrawal

Abstract

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets.

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…95,96 Given the unique role of MAGL in providing lipolytic sources of free fatty acids for the synthesis of oncogenic signaling lipids, CSCs might co-opt lipolytic enzymes such as MAGL to translate their lipogenic state of stem cells into an array of protumorigenic signals. The recent discovery that cancer adaptation to antiangiogenic treatments, which generate hypoxic and nutrient-starved tumor microenvironments that suppress cell cycle progression but enrich non-proliferating CSC, [97][98][99][100][101][102][103] involves a significant upregulation of lipid synthesis that fuels tumor regrowth and metastasis after angiogenic therapy withdrawal, 104 strongly supports the notion that key enzymes involved in lipid metabolism such as FASN could play key roles in the reprogramming of CSC cellular states.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…In vitro, in hi bi tion of ACL and FAS can de crease can cer cell mi gra tion [196], whereas fatty acid ex po sure can pro mote mi gra tion and in va sion [197]. In vivo, FAS si lenc ing or in hi bi tion with Orli s tat was re ported to de crease tu mor re growth and metasta tic bur den fol low ing with drawal of So rafenib or Suni tinib, re lapses and metas tases be ing highly de pen dent on lipid syn the sis fol low ing an tian gio genic ther a pies [7]. In col orec tal tu mor mod els, si lenc ing FAS de creased liver metas ta sis [196].…”

“…This over all com plex ity re sults in the de vel op ment of dif fer ent meta bolic adap ta tions, such as meta bolic sym bio sis [5,6], re lated to a co op er a tion be tween can cer cells with dif fer ent meta bolic needs and adap ta tion to lim ited per fu sion and aci do sis [7,8]. This meta bolic het ero gene ity is also mir rored by the bi o log i cal het ero gene ity of tu mors, where cells will have di verse meta bolic re quire ments ac cord ing to the spe cific bi o log i cal ac tiv ity oc cur ring in that par tic u lar area, e.g.…”

Metabolism: A New Frontier in Cancer Research

“…Sounni et al [19] found an increased lipid synthesis under these conditions, which, when blocked pharmacologically, inhibited the regrowth. This again strengthens the suggestion that inhibition of lipogenesis may be a way to tumor reduction.…”