CB₂R cannanoid receptor as therapeutic target and prognostic/predictive tool in HER2+brest cancer

Tesis de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 16-11-2018El cáncer de mama es una de las enfermedades más frecuentes en todo el mundo y representa un importante problema de salud pública. Se trata de una enfermedad muy heterogénea que se clasifica en distintos subtipos atendiendo a marcadores moleculares. Uno de ellos se caracteriza por la sobre expresión del receptor del factor de crecimiento epidérmico 2 (HER2), y representa un 20%-25% de todos los cánceres de mama diagnosticados. Aunque estos tumores son muy agresivos, el pronóstico de las pacientes ha mejorado enormemente con el desarrollo de terapias dirigidas contra este receptor. Sin embargo, las tasas de resistencia innata y adquirida son muy elevadas y, por tanto, sigue siendo necesaria la búsqueda de tanto nuevos tratamientos para estas pacientes, como de herramientas que permitan la identificación temprana de aquellas con alto riesgo de no responder a terapias estándar o de recaer..Breast cancer is one of the most frequent malignancies worldwide and represents an important public health problem. This disease is very heterogeneous and is subclassified in different subtypes according to molecular markers. One of them is characterized by the over expression of the human epidermal growth factor receptor 2 (HER2), and represents 20%–25% of all breast carcinomas. Although these tumors are very aggressive, the clinical outcome of HER2+ breast cancer patients has greatly improved with the development of targeted therapies against this receptor. However the innate and acquired resistance rates to these therapies are still significant and therefore, new therapies are urgently warranted for these patients as well as new tools to identify those at a higher risk of not responding or recurring...Fac. de Ciencias BiológicasTRUEunpu

Effect of molasses application alone or combined with trichoderma asperellum T-34 on Meloidogyne spp. management and soil microbial activity in organic production systems

The effect of molasses alone or combined with Trichoderma asperellum T34 Biocontrol® was assessed on Meloidogyne reproduction, disease severity, and density and activity of soil microor- ganisms in pot and field experiments. Firstly, molasses application at 1 mL m−2 was assessed in four different textured soils. Secondly, molasses application at 5, 10, 20, and 40 mL m−2, alone or combined with T34, was assessed in pot and field experiments at 10 mL m−2 in two different textured soils. The application of 1 mL m−2 of molasses was effective in reducing nematode reproduction in the loam textured soil but not in sandy clay loam, sandy loam, or clay loam textured soils. Increasing molasses dosage reduced the tomato dry shoot and fresh root weights, producing phytotoxicity at 40 mL m−2. The disease severity and nematode reproduction were reduced between 23% and 65% and 49% and 99%, respectivelyThe authors thank Departament d’Acció Climàtica, Alimentació i Agenda Rural for supporting the projects to encourage applied research on organic agri-food production (53 05004 2016 and 53 05010 2017). The authors also thank the farmers J. Montmany, F. Berenguer, J. Olivella, J. Magrans, and J. M. Mas for their support in conducting the experimentPostprint (published version

Fatty acid amide hydrolase drives adult mammary gland development by promoting luminal cell differentiation

Mammary gland development occurs primarily in adulthood, undergoing extensive expansion during puberty followed by cycles of functional specialization and regression with every round of pregnancy/lactation/involution. This process is ultimately driven by the coordinated proliferation and differentiation of mammary epithelial cells. However, the endogenous molecular factors regulating these developmental dynamics are still poorly defined. Endocannabinoid signaling is known to determine cell fate-related events during the development of different organs in the central nervous system and the periphery. Here, we report that the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) plays a pivotal role in adult mammary gland development. Specifically, it is required for luminal lineage specification in the mammary gland, and it promotes hormone-driven secretory differentiation of mammary epithelial cells by controlling the endogenous levels of anandamide and the subsequent activation of cannabinoid CB1 receptors. Together, our findings shed light on the role of the endocannabinoid system in breast development and point to FAAH as a therapeutic target in milk-production deficitsThis study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI17/00041 and PI20/00590 to CS and EP-G and co-funded by the European Union. IT is the recipient of a PFIS fellowship (from the Spanish Ministry of Economy and Competitiveness

Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

There is a subtype of breast cancer characterized by the overexpression of the oncogene HER2. Although most patients with this diagnosis benefit from HER2-targeted treatments, some do not respond to these therapies and others develop resistance with time. New tools are therefore warranted for the treatment of this patient population, and for early identification of those individuals at a higher risk of developing innate or acquired resistance to current treatments. Here, we show that HER2 forms heteromer complexes with the cannabinoid receptor CB2R, the expression of these structures correlates with poor patient prognosis, and their disruption promotes antitumor responses. Collectively, our results support HER2–CB2R heteromers as new therapeutic targets and prognostic tools in HER2+ breast cancer

Cannabinoid receptor CB2 drives HER2 pro-oncogenic signaling in breast cancer

Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different models of cancer. However, the biological role of these receptors in tumor physio-pathology is still unknown. We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen and Freiburg between 1997 and 2010. CB2 mRNA expression was also analyzed in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the HER2 rat ortholog (neu) and lacks CB2, and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by co-localization, coimmunoprecipitation and proximity ligation assays. We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis. We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade, and that an increased CB2 expression activates the HER2 prooncogenic signaling machinery at the level of the tyrosine kinase c-SRC. Finally, HER2 and CB2 form heteromers in cancer cells. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and suggest that CB2 may be a biomarker with prognostic value in these tumors

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

The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtypeThis work was supported by grants from Spanish Ministry of Economy and Competitiveness [PI11/00295 to CS, PI14/01101 to CS and EP-G, SAF2013-46183-R to MQ, and SAF2014-54705-R to MV-M, supported with European Regional Development (FEDER) funds] and Madrid Regional Government (S2010/BMD-2308 to MG, and 2010/BMD-2359 to MQ). EPG was a recipient of a Postdoctoral Research Contract from Fundación Científica Asociación Española Contra el Cáncer and a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship. SB-B and SC-L are recipients of a Formación de Profesorado Universitario (FPU) fellowship and a Ramón y Cajal research contract, respectively, from the Spanish Ministry of Economy and Competitivenes

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

[EN] Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3,4,5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes.S