Abstract 1451: A novel lipid-centrosomal axis in prostate cancer is regulated by PEDF

Abstract

Abstract Background: Prostate tumor cells undergo metabolic adaptations and revert to lipid stores to meet the energy demands of their high proliferative capacity. To fuel progression, cancer cells accumulate triacylglycerol in cytoplasmic lipid droplets (LDs) and amplify cell cycle regulators such as centrosomes and non-centrosomal microtubule organizing centers (ncMTOCs). LDs not only store lipid, they also can carry cargo using microtubules to facilitate movement of proteins to various cellular locations. It is not known whether crosstalk exists between lipid storage organelles and non-membrane bound centrosomes in prostate cancer cells or stromal cancer associated fibroblasts (CAFs). We postulated that MTOCs have a metabolic sensing function in prostate cancer cells and a lipid-enriched microenvironment facilitates a PEDF-dependent metabolic switch that directly promotes centrosomal amplification. Methods: Prostate cancer cell lines, PC-3 and LNCap, normal fibroblasts and CAFs derived from human prostate cancer specimens were analyzed for TAG regulating proteins, PEDF, adipose triglyceride lipase (ATGL), comparative gene index-58 and GO/G1 switch gene 2 by western blot and immunofluorescence (IF). Centrosomes were stained with matrix proteins, pericentrin and γ-tubulin and quantified by IF. Cells were treated with recombinant PEDF or a diacylglycerol transferase I (DGAT1) inhibitor. Lipid storage was assessed in human prostate tumor tissue from various Gleason scores (n=120) by quantifying LD density using stains for neutral lipid. Results: Normal prostate fibroblasts expressed high levels of PEDF and ATGL whereas only minimal expression of these proteins was detected in CAFs and prostate cancer cells. Cytoplasmic LD density in human prostate tumors increased progressively with disease grade. A plasticity in centrosomal amplification in CAFs and cancer cells was discovered when restoration of PEDF normalized the centrosomal number. A new lipid-centrosomal signaling axis emerged when use of a DGAT1 inhibitor to block lipogenesis suppressed LD density and concurrently reduced the centrosomal or ncMTOC number. A collaborative interaction between LDs and MTOCs was noted when LDs were found to carry centrosomal proteins, pericentrin and γ-tubulin, on their surface and lipolytic regulator PEDF co-localized with pericentrin. Conclusions: These results suggest that prostate CAFs are simultaneously keeping pace with their tumor cell partners by making both centrosomal and pro-lipogenic metabolic adaptations. Normalization of MTOCs by restoring PEDF or by blocking lipogenesis in prostate cancer cells or CAFs highlight a previously unrecognized plasticity in centrosomal biology. These data suggest that lipid-laden CAFs and tumors cells can modulate MTOC distribution and number by signaling through a new PEDF-dependent lipid-centrosomal axis. Citation Format: Francesca Nardi, Philip Fitchev, Omar E. Franco, Jelena Ivanisevic, Adrian Scheibler, Simon W. Hayward, Yuan Ji, Charles B. Brendler, Michael A. Welte, Susan E. Crawford. A novel lipid-centrosomal axis in prostate cancer is regulated by PEDF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1451.