Gene regulatory networking reveals the molecular cue to lysophosphatidic acid‐induced metabolic adaptations in ovarian cancer cells

Abstract

Extravasation and metastatic progression are two main reasons for the high mortality rate associated with cancer. The metastatic potential of cancer cells depends on a plethora of metabolic challenges prevailing within the tumor microenvironment. To achieve higher rates of proliferation, cancer cells reprogram their metabolism, increasing glycolysis and biosynthetic activities. Just why this metabolic reprogramming predisposes cells towards increased oncogenesis remains elusive. The accumulation of myriad oncolipids in the tumor microenvironment has been shown to promote the invasiveness of cancer cells, with lysophosphatidic acid (LPA) being one such critical factor enriched in ovarian cancer patients. Cellular bioenergetic studies confirm that oxidative phosphorylation is suppressed and glycolysis is increased with long exposure to LPA in ovarian cancer cells compared with non‐transformed epithelial cells. We sought to uncover the regulatory complexity underlying this oncolipid‐induced metabolic perturbation. Gene regulatory networking using RNA‐Seq analysis identified the oncogene ETS‐1 as a critical mediator of LPA‐induced metabolic alterations for the maintenance of invasive phenotype. Moreover, LPA receptor‐2 specific PtdIns3K‐AKT signaling induces ETS‐1 and its target matrix metalloproteases. Abrogation of ETS‐1 restores cellular bioenergetics towards increased oxidative phosphorylation and reduced glycolysis, and this effect was reversed by the presence of LPA. Furthermore, the bioenergetic status of LPA‐treated ovarian cancer cells mimics hypoxia through induction of hypoxia‐inducible factor‐1α, which was found to transactivate ets‐1. Studies in primary tumors generated in syngeneic mice corroborated the in vitro findings. Thus, our study highlights the phenotypic changes induced by the pro‐metastatic factor ETS‐1 in ovarian cancer cells. The relationship between enhanced invasiveness and metabolic plasticity further illustrates the critical role of metabolic adaptation of cancer cells as a driver of tumor progression. These findings reveal oncolipid‐induced metabolic predisposition as a new mechanism of tumorigenesis and propose metabolic inhibitors as a potential approach for future management of aggressive ovarian cancer.

Aberrant lipid metabolism in cancer cells – the role of oncolipid‐activated signaling

“…Additionally, LPA was found to promote the mesenchymal switch in ovarian cancer cells through suppression of the expression of histone deacetylase SIRT1, an important epithelial to mesenchymal transition regulator . Furthermore, a recent report revealed that LPA induces the aggressiveness of ovarian cancer cells through up‐regulation of the oncogene ETS‐1 leading to both increased glycolysis and cell‐type‐specific expression of MMPs, thereby imparting a persistent invasive potential on the cancer cells . Collectively, all these reports contribute to the importance of this oncolipid toward increased aggressiveness in different cancer types.…”

“…The role of LPA in tumor lipid metabolism is less well studied. LPA, being a byproduct of the metabolic pathways, has gained immense importance due to its excess production in several cancers, promoting their invasive properties . However, a single report claims that LPA enhances lipogenesis and promotes the invasiveness of ovarian cancer cells .…”

Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance

“…However, it is important to note that locally produced LPA likely reaches much higher concentrations than circulating LPA [ 9 ]. The importance of LPA in disease has been underscored by studies linking aberrant LPA signaling to a broad range of pathophysiological conditions, including cancer, arthritis, pulmonary fibrosis, neurological disorders, and obesity-induced insulin resistance and impaired glucose homeostasis [ 7 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment

“…With these chemical properties, LPLs are synthesized and/or secreted extracellularly and many of them function as signaling molecules through their specific membrane receptors. In addition, several of these LPLs have tumor promoting activities and are thus termed as “oncolipids” [ 24 ]. They are accumulated in the TME.…”