2012/09/04

The therapeutic potential of cellular fat oxidation in bone-marrow transplants and breast cancer

- Dr. Arkaitz Carracedo of Biogune takes part in two studies which provide evidence for a crucial role of the PML protein in the regulation of cellular fat oxidation, with important implications in physio-pathological processes

- The first study, published in The Journal of Clinical Investigation, suggests that PML inhibition could have therapeutic potential in a subset of breast cancers

- The second study, featured in Nature Medicine, reveals the requirement for fat oxidation, which is also regulated by PML, in the generation of blood cells from stem cells

(Bilbao, 4th September 2012) - Altered fat accumulation and metabolism in developed societies is of increasing health and aesthetic concern. There is, however, more to this process than simply the impact of lipid accumulation on the body. Lipids are one of the most concentrated energy sources known, thus making them an invaluable nutrient for our cells under challenging conditions. Despite this, little is known about the impact of fat-oxidation processes on cell fitness.

Two independent studies in which Arkaitz Carracedo, Ikerbasque Research Professor at Biogune, has taken part in collaboration with the world-leading research team headed by Pier Paolo Pandolfi at Harvard Medical School, have unravelled how known and novel components of the lipid oxidation regulation machinery impact cell and body fitness. In these studies, a well-described tumour suppressor, namely promyelocytic leukaemia protein (PML), which ensures that cells behave correctly and keeps cancer cells in check, is shown to be a new regulator of the fat-oxidation process (also known as fatty acid oxidation, or FAO). The metabolic activity of PML, in turn, reveals novel and paradoxical functions for this protein.

The first study, published in the September issue of the Journal of Clinical Investigation, defines the mechanism by which PML modulates FAO (by regulating peroxisome proliferator-activated receptors, PPARs) and shows that alterations in this pathway result in excessive fat accumulation and the development of obesity in mouse models. "Surprisingly, by regulating metabolism, PML exerts a paradoxical activity in breast cancer, where instead of keeping breast cancer cells under control, it provides a selective advantage under conditions of metabolic challenge", says Dr. Carracedo.

This observation is correlated with the increase in PML levels in a subset of breast cancer specimens and its association with poor prognosis. This study therefore provides puzzling evidence of an unexpected activity of PML in breast cancer, where, instead of keeping cancer cells under control, it provides them with the energy they need to survive. "These findings have changed our vision of PML and have led us to study whether drugs used to inhibit PML in leukaemia can also be used to treat breast cancer", adds Arkaitz Carracedo.

The second study, carried out jointly with Dr. Keisuke Ito (now at the Albert Einstein College of Medicine), has defined for the first time the contribution of lipid metabolism to the maintenance and function of haematopoietic stem cells, the source of the haematopoietic lineage. This work, published in the September issue of Nature Medicine, describes how haematopoietic stem cells require high levels of FAO in order to maintain their undifferentiated state. Indeed, the pharmacological or genetic inhibition of this metabolic pathway (which is regulated by PML and PPAR delta), means that such stem cells are no longer able to sustain blood cell supply, whereas its activation enhances the ability of these cells to replenish the haematopoietic compartment in bone marrow transplants.

"The idea that this pathway may be relevant to the function of blood stem cells is really exciting since it opens the door to the possibility that we may be able to reduce the amount of material needed for bone marrow transplants by using drugs that regulate this route. We hope that future research will determine whether such drugs can provide a benefit to the patient", says Arkaitz Carracedo.

What can we learn from these studies? First of all, fat oxidation is of tremendous relevance to both normal and cancer cells. These two studies cover the impact of the process on different aspects of biomedical research, especially obesity, breast cancer and haematopoietic stem cell maintenance. "But, more importantly, the pathway described therein is highly amenable to pharmacological manipulation. PML, PPARs and FAO can be modulated using compounds that are either already available or have already passed toxicity and tolerability evaluations in clinical trials", says Dr. Carracedo.

"As a result, understanding the relevance of this novel pathway in obesity, haematopoietic stem cell maintenance and breast cancer could potentially lead, with further investigation, to the establishment of novel pharmacological approaches to the treatment of related pathologies in the future", concludes Arkaitz Carracedo.

Bibliographic reference:

Nature Medicine:
A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance
Keisuke Ito, Arkaitz Carracedo, Dror Weiss, Fumio Arai, Ugo Ala, David E Avigan, Zachary T Schafer, Ronald M Evans, Toshio Suda, Chih-Hao Lee & Pier Paolo Pandolfi

Journal of Clinical Investigation:
A metabolic prosurvival role for PML in breast cancer
Arkaitz Carracedo, Dror Weiss, Amy K. Leliaert, Manoj Bhasin, Vincent C.J. de Boer, Gaelle Laurent, Andrew C. Adams, Maria Sundvall, Su Jung Song, Keisuke Ito, Lydia S. Finley, Ainara Egia, Towia Libermann, Zachary Gerhart-Hines, Pere Puigserver, Marcia C. Haigis, Elefteria Maratos-Flier, Andrea L. Richardson, Zachary T. Schafer and Pier P. Pandolfi