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      Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

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          Abstract

          Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.

          Abstract

          The mechanisms associated with Caveolin-1 (Cav-1) mediated metabolic changes in prostate cancer are unclear. Here, the authors show that Cav-1 promotes rewiring of cancer cell lipid metabolism towards a program of exogenous lipid scavenging and vesicle biogenesis that intersects with mitochondrial dynamics in prostate tumors.

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          Systematic variation in gene expression patterns in human cancer cell lines.

          We used cDNA microarrays to explore the variation in expression of approximately 8,000 unique genes among the 60 cell lines used in the National Cancer Institute's screen for anti-cancer drugs. Classification of the cell lines based solely on the observed patterns of gene expression revealed a correspondence to the ostensible origins of the tumours from which the cell lines were derived. The consistent relationship between the gene expression patterns and the tissue of origin allowed us to recognize outliers whose previous classification appeared incorrect. Specific features of the gene expression patterns appeared to be related to physiological properties of the cell lines, such as their doubling time in culture, drug metabolism or the interferon response. Comparison of gene expression patterns in the cell lines to those observed in normal breast tissue or in breast tumour specimens revealed features of the expression patterns in the tumours that had recognizable counterparts in specific cell lines, reflecting the tumour, stromal and inflammatory components of the tumour tissue. These results provided a novel molecular characterization of this important group of human cell lines and their relationships to tumours in vivo.
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            JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.

            Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer-derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance.
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              Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control.

              Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD.
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                Author and article information

                Contributors
                jeri.kim@merck.com
                shanash@mdanderson.org
                timthomp@mdanderson.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                27 August 2020
                27 August 2020
                2020
                : 11
                : 4279
                Affiliations
                [1 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Clinical Cancer Prevention, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                [2 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, McCombs Institute for the Early Detection and Treatment of Cancer, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                [3 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Urology, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                [4 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Genitourinary Medical Oncology, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                [5 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Biostatistics, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                [6 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Bioinformatics and Computational Biology, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                [7 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Dan L Duncan Comprehensive Cancer Center Division of Biostatistics, , Baylor College of Medicine, One Baylor Plaza, ; Houston, TX 77030 USA
                [8 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Genetics, , The University of Texas MD Anderson Cancer Center, ; 1515 Holcombe Boulevard, Houston, TX 77030 USA
                Author information
                http://orcid.org/0000-0002-6090-703X
                http://orcid.org/0000-0002-8532-8712
                http://orcid.org/0000-0003-3316-0468
                http://orcid.org/0000-0002-4210-1593
                http://orcid.org/0000-0003-1424-3831
                Article
                17645
                10.1038/s41467-020-17645-z
                7453025
                32855410
                fb4be308-c381-4cec-8808-bf0b02939e74
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 July 2019
                : 9 July 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000005, U.S. Department of Defense (United States Department of Defense);
                Award ID: W81XWH-18-1-0173
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: P30 CA16672
                Award ID: R21 CA223527
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                biochemistry,cancer,cell biology
                Uncategorized
                biochemistry, cancer, cell biology

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