Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis

Andras Ladanyi, Abir Mukherjee, Hilary A. Kenny, Alyssa Johnson, Anirban Mitra, Sinju Sundaresan, Kristin M. Nieman, Gloria Pascual, Salvador Aznar Benitah, Anthony Montag, S. Diane Yamada, Nada A. Abumrad, Ernst Lengyel

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalOncogene
DOIs
StateAccepted/In press - Feb 5 2018
Externally publishedYes

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Adipocytes
Ovarian Neoplasms
Neoplasm Metastasis
Fatty Acids
Neoplasms
Up-Regulation
Lipoma
Peritoneal Cavity
Growth
Tumor Burden
Intraperitoneal Injections
Heterografts
Energy Metabolism
Small Interfering RNA
Cultured Cells
Reactive Oxygen Species
Cholesterol
Monoclonal Antibodies
Cell Membrane
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Ladanyi, A., Mukherjee, A., Kenny, H. A., Johnson, A., Mitra, A., Sundaresan, S., ... Lengyel, E. (Accepted/In press). Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene, 1-17. https://doi.org/10.1038/s41388-017-0093-z

Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. / Ladanyi, Andras; Mukherjee, Abir; Kenny, Hilary A.; Johnson, Alyssa; Mitra, Anirban; Sundaresan, Sinju; Nieman, Kristin M.; Pascual, Gloria; Benitah, Salvador Aznar; Montag, Anthony; Yamada, S. Diane; Abumrad, Nada A.; Lengyel, Ernst.

In: Oncogene, 05.02.2018, p. 1-17.

Research output: Contribution to journalArticle

Ladanyi, A, Mukherjee, A, Kenny, HA, Johnson, A, Mitra, A, Sundaresan, S, Nieman, KM, Pascual, G, Benitah, SA, Montag, A, Yamada, SD, Abumrad, NA & Lengyel, E 2018, 'Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis', Oncogene, pp. 1-17. https://doi.org/10.1038/s41388-017-0093-z
Ladanyi, Andras ; Mukherjee, Abir ; Kenny, Hilary A. ; Johnson, Alyssa ; Mitra, Anirban ; Sundaresan, Sinju ; Nieman, Kristin M. ; Pascual, Gloria ; Benitah, Salvador Aznar ; Montag, Anthony ; Yamada, S. Diane ; Abumrad, Nada A. ; Lengyel, Ernst. / Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. In: Oncogene. 2018 ; pp. 1-17.
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AU - Sundaresan, Sinju

AU - Nieman, Kristin M.

AU - Pascual, Gloria

AU - Benitah, Salvador Aznar

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