Available online 1 April 2024, 101930
Author links open overlay panel, , , , , , , , Highlights•Cancer cells exposed to acidosis foster adipocyte lipolysis.
•Tumoral acidosis promotes β-glucuronidase, a novel prolipolytic factor.
•Neutralisation of tumoral acidosis prevents adipose tissue loss in vivo.
AbstractObjectiveTumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia.
MethodsTo evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes.
ResultsHere, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocyte and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for β-glucuronidase as a promising new actor in adipocyte lipolysis.
ConclusionsTumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for dual therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.
KeywordsTumor acidosis
Adipose tissue
Lipolysis
Adipocytes
Cancer cachexia
Beta-glucuronidase
© 2024 The Author(s). Published by Elsevier GmbH.
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