Abstract LB-278: Metabolic regulator PGC-1α promotes angiogenesis and metastasis in nutrient deprivation selected tumor cells.
Authors: Cheong Jae-Ho , Park Eun Sung , Liang Jiyong , Mills Gordon B. 
Published: August 2014

Metastasis is a leading cause of cancer related mortality thus representing the most significant problem in treating cancer. Metastatic competence requires the acquisition of multiple new properties by tumor cells including the ability to migrate and invade, survive anoikis conditions in the vasculature, and then egress and survive in the stressful environment of metastatic site. The processes leading to the acquisition of metastatic competence are poorly understood.

As the tumor progresses, the metabolic stresses in the local microenvironment including hypoxia and nutrient deprivation increases and may directly contribute to the induction of metastasis. Indeed, studies have demonstrated that tumor hypoxia leads to the selection of tumor subclones expressing HIF-1α that can survive the hypoxic environment and induce angiogenesis thereby facilitating invasion and metastasis. However, it is unknown whether a lack of nutrients, particularly glucose deprivation in the tumor microenvironment, would contribute to the emergence of metastatic competence. Thus, we have conducted the current study with a central hypothesis that tumor environmental metabolic stress could function as a selective pressure in the emergence of metastagenic subclone. Here we demonstrate that cells selected for ability to survive metabolic stress in vitro acquire and maintain metastatic competence. We devised an in vitro culture model system which mimics the Warburg effect with depletion of glucose in the tumor microenvironment to recapitulate the environmental stress-driven selection process. Selected cells demonstrated a marked increase in invasiveness and colony forming capacity. In vivo tumorigenicity was also drastically increased with both increased number and size of xenografts and a marked increase in metastatic sites. Genome-wide transcriptional profiling and subsequent gene set analysis implicated mitochondrial biogenesis, lipid metabolism and oxidative phosphorylation of ATP synthesis in the increased metastatic capacity of selected cells. We identified peroxisome proliferator-activated receptor gamma coactivator 1 α (PGC-1α), a critical metabolic sensor and transcriptional coregulator of oxidative metabolism, as a key molecular player mediating the transcriptional reprogramming and the emergence of metastatic subclone. Knock down of PGC-1α repressed the expression of VEGF and other angiogenic factors, metastasis, and the in vitro selection process itself, consistent with an indispensable role of PGC-1α in emergence of metastatic competence. The ability of metabolic stress in vitro to select cells with constitutive upregulation of PGC-1α engendering metastatic competence provides new insights into how metabolic stress and subsequent metabolic reprogramming could coordinately facilitate successful metastasis.

Citation Format: Jae-Ho Cheong, Eun Sung Park, Jiyong Liang, Gordon B. Mills. Metabolic regulator PGC-1α promotes angiogenesis and metastasis in nutrient deprivation selected tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2013-LB-278