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Investigating the Role of Class-1 PI3K signaling in Obesity-Mediated Tumor Promotion: the interplay between fat metabolism, inflammatory cells and angiogenesis

English title Investigating the Role of Class-1 PI3K signaling in Obesity-Mediated Tumor Promotion: the interplay between fat metabolism, inflammatory cells and angiogenesis
Applicant Rüegg Curzio Roberto
Number 154499
Funding scheme Sinergia
Research institution Unité de Pathologie Faculté de Science et Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Experimental Cancer Research
Start/End 01.06.2015 - 30.06.2018
Approved amount 1'685'868.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Physiology : other topics

Keywords (5)

Inflammation; Cancer; Obesity; Angiogenesis; Metabolism

Lay Summary (French)

Lead
Role de la voie de signalisation des PI3 kinases dans la tumorigénèse induite pas l'obesitée.
Lay summary

L'obésité est un facteur de risque majeur pour plusieurs types de cancers, y compris le foie et le cancer du sein post-ménopausique. Il s’agit d’un important problème de santé publique en raison de la proportion importante et croissante de pandémie de l'obésité. L'obésité est également un facteur de mauvais pronostic avec un impact sur les traitements du cancer et des résultats. En dépit de l'importance clinique, le mécanisme par lequel l'obésité favorise l'initiation et la progression du cancer reste largement insaisissable. Des cellules inflammatoires recrutées au site de la tumeur primaire contribuent aux événements inflammatoires favorisant l'initiation et la progression tumorale. La formation de vaisseaux tumoraux (angiogenèse tumorale), favorise la croissance de la tumeur primaire et la formation de métastases. Dans ce projet les chercheurs Dr C. Rüegg, Dr G. Solinas et Dr V. Djonov unissent leurs forces pour étudier les mécanismes dépendants de l'hôte de l'initiation et la promotion tumorale obésité médiation.

Dans ce projet, nous allons étudier le rôle de PI3K, un enzyme essentiel dans les mécanismes de modulation du métabolisme, l'obésité, l'inflammation, l'angiogenèse et le cancer dans la promotion et progression du cancer du fois et du sein.

Les résultats obtenus dans ce projet auront des implications importantes vers une meilleure compréhension des mécanismes de l'initiation et de la progression cancereuse, qui peut être fondamental pour une meilleure prévention ou le traitement du cancer pour les personnes en surpoids et obèses.

 

 

Direct link to Lay Summary Last update: 02.06.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Splitting of circulating red blood cells as in vivo -mechanism of erythrocyte maturation in developing zebrafish, chick and mouse embryos
Brönnimann Daniel, Annese Tiziana, Gorr Thomas A., Djonov Valentin (2018), Splitting of circulating red blood cells as in vivo -mechanism of erythrocyte maturation in developing zebrafish, chick and mouse embryos, in The Journal of Experimental Biology, jeb.184564-jeb.184564.
PI3Kγ ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic β-cell apoptosis
Breasson Ludovic, Sardi Claudia, Becattini Barbara, Zani Fabio, Solinas Giovanni (2018), PI3Kγ ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic β-cell apoptosis, in The FASEB Journal, 32(1), 319-329.
The role of PI3Kgamma in metabolism and macrophage activation
Solinas Giovanni, Becattini Barbara (2017), The role of PI3Kgamma in metabolism and macrophage activation, in Oncotarget, 8(63), 106145-106146.
Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway
Hlushchuk Ruslan, Styp-Rekowska Beata, Dzambazi Jehona, Wnuk Monika, Huynh-Do Uyen, Makanya Andrew, Djonov Valentin (2017), Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway, in PLOS ONE, 12(8), e0182813-e0182813.
JNK at the crossroad of obesity, insulin resistance, and cell stress response.
Solinas Giovanni (2017), JNK at the crossroad of obesity, insulin resistance, and cell stress response., in Mol Metab, 6(2), 174-184.
PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity.
Breasson Ludovic, BecattiniBarbara, SardiClaudia, MolinaroAngela, ZaniFabio, MaroneRomina, BotindariFabrizio, BousquenaudMélanie, RueggCurzio, WymannMatthias, SolinasGiovanni (2017), PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity., in Science signaling, eaaf2969-eaaf2969.
Tumor Angiogenesis Assays
Hlushchuk Ruslan, Barré Sébastien, Djonov Valentin (2016), Tumor Angiogenesis Assays.
Modeling the Behavior of Red Blood Cells within the Caudal Vein Plexus of Zebrafish
Djukic Tijana R., Karthik Swapna, Saveljic Igor, Djonov Valentin, Filipovic Nenad (2016), Modeling the Behavior of Red Blood Cells within the Caudal Vein Plexus of Zebrafish, in Frontiers in Physiology, 7, 1-12.
JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage.
Becattini Barbara, ZaniFabio, SardiClaudia, D'AgostinoVito Giuseppe, ChooMin-Kyung, ProvenzaniAlessandro, ParkJin Mo, SolinasGiovanni (2016), JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage., in FASEB J., ((9)), 3124-3132.

Collaboration

Group / person Country
Types of collaboration
Dr. Elia Biganzoli, Universita di Milano Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Albert Santamaria Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Alessandro Provenzani, University of Trento Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Katharina Roeck, University Klinukum Eppendorf, Hamburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Matthias Paul Wymann, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Chrsitine Desmedt, ULB, Bruxelles Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EUROPEAN SOCIETY FOR CLINICAL INVESTIGATION Talk given at a conference Proinflammatory kinases in obesity-driven macrophage activation 17.05.2017 Genoa, Italy Solinas Giovanni;


Associated projects

Number Title Start Funding scheme
159824 Mechanisms of therapeutic control and escape of breast cancer metastasis 01.05.2015 Project funding (Div. I-III)
179248 Unravelling mechanisms of metastatic dormancy and colonization in breast cancer 01.05.2018 Project funding (Div. I-III)
135738 Unraveling mechanisms of brest cancer metastasis 01.03.2012 Project funding (Div. I-III)

Abstract

Obesity is a major risk factor for several cancers including of the colon, endometrium, pancreas, prostate, liver and post-menopausal breast cancer. The impact of obesity on cancer is a major public health concern because of the large and growing pandemic proportion of obesity. In addition obesity is a negative prognostic factor with impact on cancer treatments and outcome. For the future it will be of the utmost importance to identify cancer treatments specifically tailored for overweight and obese patients. In spite of the clinical relevance, the mechanism by which obesity promotes cancer initiation and progression remains largely elusive. Although cancer initiation and progression requires the activation of tumor promoting genes (oncogenes) and the inactivation of tumor suppressor genes through genetic and epigenetic events, additional factors within the host provide an important and some times essential contribution to tumorigenesis. Bone marrow-derived inflammatory cells newly recruited at the tumor site and resident leukocytes are instrumental to inflammatory events contributing to tumor initiation and progression. The formation of a tumor-associated vasculature, a process also know as tumor angiogenesis, facilitates primary tumor growth and metastasis formation. In this project three established investigators, Pr C. Rüegg, Dr. G. Solinas and Pr V. Djonov with related but complementary research interests and expertise are joining forces to investigate host-dependent mechanisms of obesity-mediated tumor initiation and promotion. PI3K-Akt is a critical signaling node in mechanisms modulating metabolism, obesity, inflammation, angiogenesis and cancer relevant to obesity-mediated tumor promotion. In this project we will generate and use mice lacking three different isozymes of PI3K (beta, gamma, delta) in hematopoietic/inflammatory and endothelial cells, to test the role of these PI3K isozymes in obesity mediated promotion of hepatocellular carcinoma, breast cancer progression and metastasis, and intussusceptive angiogenesis. The specific subprojects are:1) Investigating the role of PI3K signaling in obesity-mediated promotion of hepatocellular carcinoma (Solinas)2) Role of class-1 PI3K signaling within hematopoietic and endothelial cells in obesity-mediated breast cancer progression (Rüegg)2) Intussusceptive angiogenesis - an alternative way of blood vessel formation in obesity driven tumor initiation and progression (Djonov)We envisage that results obtained in this project will have important implications toward a better understanding of the mechanisms of cancer initiation and progression, which may be fundamental to better tumor prevention or cancer treatment for overweight and obese individuals.
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