Poster Presentation 30th Lorne Cancer Conference 2018

Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer (#118)

Clara Andradas Arias 1 2 , Sandra Blasco-Benito 2 3 , Sonia Castillo-Lluva 2 , Patricia DillenburgPilla Dillenburg-Pilla 4 , Rebeca Diez-Alarcia 5 , Alba Juanes-García 6 , Elena García-Taboada 2 , Rodrigo Hernando-Llorente 2 , Joaquim Soriano 7 , Sigrid Hamann 8 , Antonia Wenners 8 , Ibrahim Alkatout 8 , Wolfram Klapper 9 , Christoph Rocken 9 , Maret Bauer 8 , Norbert Arnold 8 , Miguel Quintanilla 10 , Diego Megías 7 , Miguel Vicente-Manzanares 6 , Leyre Urigüen 5 , J. Silvio Gutkind 4 11 , Manuel Guzmán 2 12 , Eduardo Pérez-Gómez 2 3 , Cristina Sanchez 2 3
  1. Telethon Kids Institute, Nedlands, WA, Australia
  2. Department of Biochemistry and Molecular Biology I, School of Biology,, Complutense University, Madrid, Spain
  3. Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
  4. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
  5. Department of Pharmacology, University of The Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain, Vizcaya, Spain
  6. School of Medicine, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa and Universidad Autónoma de Madrid, Madrid, Spain
  7. Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  8. Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, , Kiel, Germany
  9. Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
  10. Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
  11. Department of Pharmacology, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
  12. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

Different studies have shown that cannabinoids, the active components of the plant Cannabis sativa and their derivatives, exhibit anti-tumour effects by targeting different stages of tumour progression. These effects are mediated by the activation of specific receptors. So far, two cannabinoid receptors have been characterized, CB1 and CB2, but different reports suggest the existence of other endocannabinoid receptors. These two cannabinoid receptors (CB1 and CB2), their endogenous ligands and the enzymes that produce and metabolize these ligands is known as the endocannabinoid system (ECS). The ECS is a cell communication system that participates in the control of different physiological functions, and it has been shown that it is deregulated in a variety of cancers.  The orphan G protein-coupled receptor GPR55 has been proposed as one of these new cannabinoid receptors, where a number of cannabinoids can bind and modulate its activity, although L-α-lysophosphatidylinositol (LPI) seems to be the most potent endogenous ligand.

Emerging evidence point to an important role of GPR55 in tumour generation and growth. Thus, GPR55 has been directly or indirectly related to the basic alterations that drive cancer cell fate and malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis and cancer cell adhesion and migration. However, little is known about the role of GPR55 in metastasis, the last and most lethal step during tumour progression. In this work, we studied whether GPR55 participates in the control of the metastatic process. Our results show that high GPR55 expression in human tumours is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and poor patient prognosis. Activation of GPR55 confers pro-invasive features on breast cancer cells both in vitro and in vivo via Gq/11 heteromeric G proteins, ERK and the activation of the transcription factor ETV4/PEA3. Together, our data support the involvement of GPR55 on cancer metastasis, and suggest that pharmacological blockade of this receptor could be a new strategy to manage metastatic breast cancer.