PEDF regulates plasticity of a novel lipid-MTOC axis in prostate cancer associated fibroblasts

Prostate tumors make metabolic adaptations to ensure adequate energy and amplify cell cycle regulators such as centrosomes to sustain their proliferative capacity. It is not known whether cancer associated fibroblasts (CAFs) undergo metabolic re-programming. We postulated that CAFs augment lipid storage and amplify centrosomal or non-centrosomal microtubule organizing centers (MTOCs) through a pigment epithelium-derived factor (PEDF)-dependent lipid-MTOC signaling axis. Primary normal human prostate fibroblasts (NFs) and CAFs were evaluated for lipid content, triacylglycerol-regulating proteins, MTOC number and distribution. CAFs were found to store more neutral lipids than NFs. Adipose triglyceride lipase (ATGL) and PEDF were strongly expressed in NFs while CAFs had minimal to no detectable PEDF or ATGL protein. At baseline, CAFs demonstrated MTOC amplification when compared to 1-2 perinuclear MTOCs consistently observed in NFs. PEDF treatment or blockade of lipogenesis suppressed lipid content and MTOC number. In summary, our data support that CAFs have acquired a tumor-like phenotype by re-programming lipid metabolism and amplifying MTOCs. Normalization of MTOCs by restoring PEDF or by blocking lipogenesis highlights a previously unrecognized plasticity in centrosomes regulated by a new lipid-MTOC axis.

Journal of cell science. 2018 May 23 [Epub ahead of print]

Francesca Nardi, Philip Fitchev, Omar E Franco, Jelena Ivanisevic, Adrian Scheibler, Simon W Hayward, Charles B Brendler, Michael A Welte, Susan E Crawford

Department of Surgery, NorthShore University Research Institute, Affiliate of University of Chicago Pritzker School of Medicine, Evanston, IL 60201, USA., Department of Biology, University of Rochester, Rochester, NY 14627, USA., Department of Surgery, NorthShore University Research Institute, Affiliate of University of Chicago Pritzker School of Medicine, Evanston, IL 60201, USA .

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