2. Academic Validation
  3. Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

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

  • Nat Commun. 2020 Aug 27;11(1):4279. doi: 10.1038/s41467-020-17645-z.
Jody Vykoukal  # 1 2,  Johannes F Fahrmann  # 1,  Justin R Gregg 3,  Zhe Tang 4,  Spyridon Basourakos 4,  Ehsan Irajizad 5,  Sanghee Park 4,  Guang Yang 4,  Chad J Creighton 6 7,  Alia Fleury 1,  Jeffrey Mayo 1,  Adriana Paulucci-Holthauzen 8,  Jennifer B Dennison 1,  Eunice Murage 1,  Christine B Peterson 5,  John W Davis 3,  Jeri Kim 9,  Samir Hanash 10 11,  Timothy C Thompson 12
Affiliations

Affiliations

  • 1 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
  • 2 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 Department of Urology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
  • 4 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
  • 5 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
  • 6 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
  • 7 Dan L Duncan Comprehensive Cancer Center Division of Biostatistics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
  • 8 Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
  • 9 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. [email protected].
  • 10 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. [email protected].
  • 11 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. [email protected].
  • 12 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. [email protected].
  • # Contributed equally.
PMID: 32855410 DOI: 10.1038/s41467-020-17645-z
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.

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