Molecular Oncology

TITLE: 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 behind the high mortality rate associated with cancer. The metastatic potential of cancer cells depends on a plethora of metabolic challenges prevailing in the tumor microenvironment. To achieve higher proliferative rates, 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 (OC) patients. Cellular bioenergetic studies confirm that oxidative phosphorylation is suppressed and glycolysis is increased with long exposure to LPA in OC cells compared to 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 the LPA-induced metabolic alterations for the maintenance of invasive phenotype. Moreover, LPAR2-receptor-specific PI3K-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 OC cells mimics hypoxia through induction of HIF-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 OC cells. The relationship between enhanced invasiveness and metabolic plasticity further illustrates a 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 OC.

AUTHORS: Upasana Ray, Shreya Roy Chowdhury, Madavan Vasudevan, Kiran Bankar, Susanta Roychoudhury, Sib Sankar Roy

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