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Adipocyte exosomes promote tumor aggressiveness

Research into the signals involved in the communication between adipocytes and cancer cells has been limited, until now, to the study of secreted soluble factors. Recently, a new mode of intercellular communication involving small vesicles called exosomes, has been demonstrated. These vesicles carry a variety of molecules (proteins, nucleic acids and lipids) and can transfer them to other cells, thus modifying their behavior. Recent evidence demonstrates that exosomes play a pivotal role in local and systemic cell-cell communication in cancer. For instance, melanoma-derived exosomes are involved in communication between tumor cells (Lazar et al, Pigment Cell & Melanoma Research, 2015), preparation of the pre-metastatic niche, and induction of angiogenesis, immune-cell death and immune tolerance.

Like almost all cell types, adipocytes secrete vesicles. Very little data are available concerning the composition and function of adipocyte exosomes, and the role of these vesicles in cancer had never been investigated. Hence, we studied the effect of these vesicles on melanoma progression, a tumor type that has been shown to be adversely affected by obesity (for review Clement et al, Pigment Cell & Melanoma Research, 2017).

muller_topic03-02.jpgDialogue between adipocytes and tumor cells. Adipocytes secrete exosomes that are taken up by the tumor cells, inducing a metabolic reprogramming. The tumor cells become more aggressive. The increased number and size of adipocytes in the fatty tissue of obese individuals increases the number and the activity of adipocyte exosomes, exacerbating their deleterious effect. © Laurence Nieto

We have shown that mature adipocytes secrete large amounts of exosomes that are taken up by tumor cells, leading to increased migration and invasion (and therefore their ability to form metastases). Using mass spectrometry, we analyzed the adipocyte exoproteome. Adipocyte exosomes carry many proteins implicated at different levels of lipid metabolism (transport, storage and utilization by fatty acid oxidation), a feature that is highly specific to adipocyte-derived exosomes. In agreement with a functional transfer of these proteins between adipocytes and tumor cells, we have shown that adipocyte exosomes impact lipid metabolism in cancer cells, particularly through an increase in fatty acid oxidation. Inhibition of this metabolic pathway in tumor cells completely abrogates the increase in migration/invasion observed in the presence of adipocyte-derived exosomes. Therefore, our results clearly demonstrate that adipocyte exosomes induce a metabolic remodeling in favor of fatty acid oxidation, which promotes cancer cell invasion.

In a context of obesity, we have shown that adipocytes isolated from human and murine adipose tissue secrete an increased number of vesicles compared to those from lean subjects. Moreover, these vesicles are also qualitatively different as their effect on cancer cell invasion, when used at equal concentrations, is dramatically increased. In both lean and obese conditions, inhibition of FAO completely reverses the effect of primary adipocyte exosomes on tumor cell migration, showing that FAO is involved in the obesity-associated exacerbation of this deleterious metabolic reprogramming. (Lazar et al, Cancer Research, 2016).

These results suggest that adipocyte-derived exosomes could be partly responsible for the poor prognosis of obese cancer patients. Understanding the role of adipocyte exosomes could contribute to the development of new strategies for cancer treatment involving FAO inhibitors. Such molecules, for example trimetazidine, are currently used in the context of other diseases such as angina pectoris.

Principal investigator:

Laurence Nieto

Other staff involved:

Emily Clement, Stéphanie Dauvillier

Selected publications

Lazar I, Clement E, Ducoux-Petit E, Denat L, Soldan V, Dauvillier S, Balor S, Burlet-Schiltz O, Larue L, Muller C, Nieto L.(2015) Proteome characterization of melanoma exosomes reveals a specific signature for metastatic cell lines. Pigment Cell & Melanoma Research 28:464-75.

Lazar I, Clement E, Milhas D, Ducoux-Petit M, Dauvillier S, Le Gonidec S, Soldan V, Ortega N, Balor S, Valet P, Burlet-Schiltz O, Golzio M, Muller C, Nieto L. 2016 Adipocyte-derived exosomes promote tumor cell migration: a new mechanism linking obesity and cancer Cancer Research 76 :4051-7.

Clement E, Lazar I, Muller C and Nieto L. Obesity and melanoma: Could fat be fueling malignancy? Pigment Cell & Melanoma Research, in press

Collaborators

Pr Philippe Valet’s group at the Institute of Metabolic and Cardiovascular diseases (I2MC), Toulouse (see Adipolab web page http://adipolab.weebly.com/)

Dr Lionel Larue, centre de Recherches Institut Curie, Orsay