Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation

Rhona Aird, Jimi Wills, Katherine F. Roby, Cecile Benezech, Roland H Stimson, Martin Wabitsch, Jeffrey William Pollard, Andy Finch, Zoi Michailidou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Objective: Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth.

Methods: Human and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC/MS.

Results: Hypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1α expression in adipocytes, as mouse adipocytes lacking HIF1α showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells.

Conclusion: Here, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.
Original languageEnglish
Article number989523
Number of pages12
JournalFrontiers in Endocrinology
Publication statusPublished - 18 Oct 2022

Keywords / Materials (for Non-textual outputs)

  • hypoxia
  • adipocytes
  • cancer cells
  • metabolites
  • lipids
  • obesity


Dive into the research topics of 'Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation'. Together they form a unique fingerprint.

Cite this