Fondation MEDIC

www.fondation-medic.ch

Unraveling mechanisms of breast cancer dormancy
[19.10.2016]
Project leader – Curzio Ruegg
Curzio Ruegg

Dr. Curzio Ruegg received his MD from the University of Basel in 1985. He trained in immunology in Basel, internal medicine in Bellinzona, and in cell biology at University of California at San Francisco (UCSF). In 1993 he joined the Multidisciplinairy Oncology Center at the University Hospital. In 2003 he was appointed associate professor and ISREC affiliated member, and in 2006 Head of the Division of Experimental Oncology UNIL-CePO-CHUV. He has pioneered translational cancer research in the field of anti-angiogenesis in Lausanne. In 2009 he moved to the University of Fribourg as Chair and Professor of Pathology. He has been President of the Department of Medicine from 2011 to 2013.

His research focuses on experimental and translational aspects of tumor angiogenesis and cancer metastasis, including the study of the adaptive response of the tumor and its microenvironment to anti-cancer therapies.

Dr. Regg coordinated the angiogenesis program at the National Center for Competence in Research (NCCR), Molecular Oncology. He is or was member of European Networks (TUMIC, SmArt, SmArteR) and international scientific boards (e.g. UICC, INSERM, DFG, CRUK, ESO, SENDO). He co-organized several international conferences at Centre Stefano Franscini in Ascona, Switzerland, and at European School of Hematology (ESH, Paris) in the field of angiogenesis and cancer.

He is deputy-director of the new NCCR program (2014- 2017) in stimuli-responsive materials (Leading house : University of Fribourg (http://www.bioinspired-materials.ch )

Department of Medicine,
Faculty of Science
1, Route Albert Gockel
CH-1700 Fribourg

E-Mail: curzio.ruegg@unifr.ch

Laboratory web page

Group members
 

Marie Tamm

Secretary

Grgory Bieler PhD

lab manager

Albert Santamaria PhD

Ambizione Fellow

Girieca Lorusso PhD

Maitre Assitante

Jelena Zaric PhD

Senior assistant

Laurent Ramont

Visiting scientist

Lavinai Alberi

Associate PI

Chiara Secondini PhD

Postdoctoral fellow

Melanie Bousquenaud

Postdoctoral fellow

Yu-Ting Huang

Postdoctoral fellow

Sarah Cattin

Research associate

Emanuel Lubart

Research associate

Christof Wyss

Graduate student

Begoa Alday

Graduate student

Corine Reis

Graduate student

Sarah Rafiee

Graduate student

Nathalie Duffey

Technician

Oriana Coquoz

Technician

Ashot Sargsyan

Animal Care Taker

Simone Eichenberger

Animal Care Taker

Project description
 

The main research interest of the Regg laboratory is the study of the interactions between the tumor and its host. Growing evidence indicates that carcinogenesis and tumor progression are not simply cell autonomous processes, but rather a condition involving multiple heterotypic multi-cellular interactions between cancer cells and their microenvironment. Hence, the concept of tumor microenvironment as an integrated and essential part of the tumor tissue was coined. Today the tumor microenvironment is considered as a therapeutic target with great potential for new therapeutic approaches. Hence, the interest in unraveling molecular mechanisms of bidirectional communication.

The tumor microenvironment. Tumor cells orchestrate directly (e.g. through the release of factors) or indirectly (though the induction of tissue hypoxia or appearance of necrosis) the modification of the microenvironment by attracting or activating many non-tumoral cells, including blood and lymphatic endothelial cells and pericytes, carcinoma associated fibroblast, bone marrow-derived cells, immune and inflammatory cells. Tumor cells can also deposit or modify the extracellular matrix. Most of these stromal modifications start early during tumor progression, often at the transition stage from premalignant to malignant lesion. In some cases they may even precede cancer formation, for example in situations of chronic inflammation. In turn, tumor microenvironmental events promote tumor progression by stimulating tumor growth and survival, and facilitating invasion and metastasis. Collectively these events will contribute to determine the outcome of tumor progression: tumor growth, tumor dormancy, tumor invasion and metastasis and resistance to therapy (Figure 1).

figure 1

Tumor adaptation and evasion from therapy. There is growing evidence that therapeutic interventions such as surgery, chemotherapy or bone marrow supportive treatments aimed at counterbalancing toxic effects of chemotherapy, may promote tumor progression. It is therefore possible that anti-cancer therapy when it fails, it may actually push the tumors toward a more aggressive behavior.

figure 2

We should start considering the possibility that anti-cancer treatment, if not sufficiently effective, may exert additional selective pressure on the tumor cells and the tumor microenvironment resulting in the accelerated appearance cells with increased metastatic capacities.

In the laboratory we are addressing the following questions:

  • Tumor microenvironment: How do cells of the microenvironment, in particular bone marrow-derived cells promote tumor progression? How do therapeutic interventions modify the tumor microenvironment and how do these modifications impact tumor behavior?
  • Tumor metastasis: How does the cross-talk between tumor cells and the microenvironment evolve during tumor progression toward metastasis? Is there a hierarchy of metastatic cells within the primary tumor, and how can we identify them?
  • How do tumors adapt and evade anticancer therapies. How do tumors and the microenvironment react to anticancer therapies, in particular anti-angiogenic therapies, chemotherapy and radiotherapy, and what are the consequences to tumor progression?

Results issued from this program have the potential to give rise to new therapeutic approaches with potential applications to patients. Considering the clinical relevance of the addressed questions, we expect that some of the obtained results will have translational and clinical relevance. They are likely to identify approaches to prevent cancer formation and progression including metastasis formation, for example by impinging on the formation of the pre-metastatic niche. In view of potential clinical applications, the main applicant has extensive experience in translational studies and is well connected with various oncology units in Switzerland and abroad.

Publications
 
2015 / 10.1016/j.molonc.2015.04.003
Asparuhova MB, Secondini C, Regg C, Chiquet-Ehrismann R. Mechanism of irradiation-induced mammary cancer metastasis: A role for SAP-dependent Mkl1 signaling. Mol Oncol. 2015 Oct;9(8):1510-27
PubMed
2015 / 10.1007/s10456-015-9470-9.
Fagiani E, Bill R, Pisarsky L, Ivanek R, Regg C, Christofori G. An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models. Angiogenesis. 2015 Jul;18(3):327-45.
PubMed
2015
Filipovic N, Ghimire K, Saveljic I, Milosevic Z, Ruegg C. Computational modeling of shear forces and experimental validation of endothelial cell responses in an orbital well shaker system. Comput Methods Biomech Biomed Engin. 2015 Jun 22:1-10. [Epub ahead of print]
PubMed
2015 / 10.1371/journal.pone.0123904
Ciarloni L, Hosseinian S, Monnier-Benoit S, Imaizumi N, Dorta G, Ruegg C; DGNP-COL-0310 Study Group. Discovery of a 29-gene panel in peripheral blood mononuclear cells for the detection of colorectal cancer and adenomas using high throughput real-time PCR. PLoS One. 2015 Apr 13;10(4):e0123904
PubMed
2015 / 10.18632/oncotarget.6411.
Huang YT, Lan Q, Ponsonnet L, Blanquet M, Christofori G, Zaric J, Regg C. The matricellular protein CYR61 interferes with normal pancreatic islets architecture and promotes pancreatic neuroendocrine tumor progression. Oncotarget. 2015 Nov 27
PubMed
2015
Knuchel S, Anderle P, Werfelli P, Diamantis E, Regg C. Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion. Oncotarget. 2015 Jun 10;6(16):14300-17.
PubMed
2014 / 10.1111/apt.12618
Nichita C, Ciarloni L, Monnier-Benoit S, Hosseinian S, Dorta G, Regg C. A novel gene expression signature in peripheral blood mononuclear cells for early detection of colorectal cancer. Aliment Pharmacol Ther. 2014;39(5):507-17.
PubMed
2014 / 10.1002/jlcr.3190
Monaco A, Michelin O, Prior J, Regg C, Scapozza L, Seimbille Y. Synthesis of a non-peptidic PET tracer designed for α5β1 integrin receptor. J Labelled Comp Radiopharm. 2014 May 15;57(5):365-70
PubMed
2014 / doi: 10.1002/ijc.28674
D. Barras, G. Lorusso, C. Regg. Widmann Inhibition of cell migration and invasion mediated by the TAT-RasGAP317-326 peptide requires the DLC1 tumor suppressor. Oncogene. 2014;33(44):5163-72
PubMed
2014
Lohri C, Schaltegger CS, VAN DEN Broek M, Wenger RH, Ruegg C, Fink D, Fehr MK, Knuth A, Zweifel M.. Neutrophil expression of ICAM1, CXCR1, and VEGFR1 in patients with breast cancer before and after adjuvant chemotherapy.. Anticancer Res. 2014 Sep;34(9):4693-9.
PubMed
2014 / 10.1002/ijc.28674
Barras D, Lorusso G, Lhermitte B, Viertl D, Regg C, Widmann C. Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression. Int J Cancer. 2014 Jul 1;135(1):242-7.
PubMed
2014 / 10.1371
N. Guex, I. Crespo, S. Bron, A. Ifticene-Treboux, E. Faes vant Hul, S. Kharoubi, R. Liechti1, P. Werffeli, M. Ibberson, F. Majo, M. Nicolas, J. Laurent, A. Garg, K. Zaman, H-A. Lehr, B. J. Stevenson1, C. Regg, G. Coukos, J.-F. Delaloye, I. Xenarios and M.-A. Doucey. Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches. PLOS Computational Biology
PubMed
2014 / PMID: 25202046
C. Lohri, CS Schaltegger, M. Van Den Broek, R.H. Wenger, C. Ruegg, D. Fink, M.K. Fehr, A. Knuth, M. Zweifel. Neutrophil expression of ICAM1, CXCR1, and VEGFR1 in patients with breast cancer before and after adjuvant chemotherapy. Anticancer Res. 2014 34(9): 4693-9.
PubMed
2013 / doi: 10.1002/ijc.27940
Ten Hagen TL, Seynhaeve AL, de Wiel-Ambagtsheer Ga, de Bruijn EA, van Tiel ST, Regg C, Meyring M, Grell M, Goodman SL, Eggermont AM. The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model. Int J Cancer. 2013;132(11):2694-704
PubMed
2013 / 10.1038/onc.2013.465
A. Monaco, V. Zoete, G.C. Alghisi, C. Regg, O. Michelin, J. Prior, L. Scapozza, Y. Seimbille. Synthesis and in Vitro Evaluation of a Novel radioligand for αvβ3 Integrin Receptor Imaging: [18F]FPPA-c(RGDfK). Bioorg. & Med. Chem. Letters, 2013 23(22):6068-72
PubMed
2013 / doi: 10.1038/modpathol.2012.140
Lehr HA, Rochat C, Schaper C, Nobile A, Shanouda S, Vijgen S, Gauthier A, Obermann E, Leuba S, Schmidt M, Regg C, Delaloye JF, Simiantonaki N, Schaefer SC. Mitotic figure counts are significantly overestimated in resection specimens of invasive breast carcinomas. Mod Pathol. 2013 Mar;26(3):336-42
PubMed
2012 / 10.1016/j.semcancer.2012.03.007
Lorusso G, Regg C. New insights into the mechanisms of organ-specific breast cancer metastasis. Semin Cancer Biol 2012;22:226-33
PubMed
2012 / doi: 10.1158/2159-8290.CD-11-0270
Xue G, Restuccia DF, Lan Q, Hynx D, Dirnhofer S, Hess D, Regg C, Hemmings BA. Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-β signaling axes. Cancer Discov. 2012;2(3):248-59.
PubMed
2012
Kuonen F, Laurent J, Secondini C, Lorusso G, Stehle JC, Rausch T, Faes-Van't Hull E, Bieler G, Alghisi GC, Schwendener R, Andrejevic-Blant S, Mirimanoff RO, Regg C. Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy. Clin Cancer Res. 2012;18:4365-74
PubMed
2012 / 10.1158/1078-0432
Kuonen F, Secondini C, Regg C. Molecular pathways: emerging pathways mediating growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. Clin Cancer Res 2012;18:5196-202
PubMed
2012 / http://dx.doi.org/10.1016/j.mednuc.2012.07.010
Deshayes E, Dunet V, Regg C, Prior JO. Neoangiogenesis imaging in nuclear medicine. Mdecine Nuclaire 2012;36: 61926
PubMed
2012 / 10.1016/j.semcancer.2012.02.007
Sleeman JP, Christofori G, Fodde R, Collard JG, Berx G, Decraene C, Regg C. Concepts of metastasis in flux: the stromal progression model. Semin Cancer Biol. 2012;22:174-86
PubMed
2012 / 10.1038/onc.2011.356
Carrascosa C, Obula RG, Missiaglia E, Lehr HA, Delorenzi M, Frattini M, Regg C, Mariotti A. MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells. Oncogene. 2012 Mar 22;31(12):1521-32
PubMed
2012 / 10.1038/onc.2011.218
Zaric J, Joseph JM, Tercier S, Sengstag T, Ponsonnet L, Delorenzi M, Regg C. Identification of MAGI1 as a tumor suppressor protein induced by COX-2 inhibitors in colon cancer cells. Oncogene 2012; 31: 4859
PubMed
2011 / 10.1158/0008-5472.CAN-10-3684
Laurent J, Hull EF, Touvrey C, Kuonen F, Lan Q, Lorusso G, Doucey MA, Ciarloni L, Imaizumi N, Alghisi GC, Fagiani E, Zaman K, Stupp R, Shibuya M, Delaloye JF, Christofori G, Regg C. Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors. Cancer Res. 2011 Jun 1;71(11):3781-91
PubMed
2011 / 10.1387/ijdb.103228jl
Laurent J, Touvrey C, Botta F, Kuonen F, Regg C. Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells. Int. J. Dev. Biol. 2011; 55(4-5):527-34
PubMed
2010
Chouaib S, Kieda C, Benlalam H, Noman MZ, Mami-Chouaib F, Regg C. Endothelial cells as key determinants of the tumor microenvironment: interaction with tumor cells, extracellular matrix and immune killer cells. Crit Rev Immunol. 2010;30(6):529-45
PubMed
2010 / 10.1371/journal.pone.0011084
Imaizumi N, Monnier Y, Hegi M, Mirimanoff RO, Regg C. Radiotherapy suppresses angiogenesis in mice through TGF-betaRI/ALK5-dependent inhibition of endothelial cell sprouting. PLoS One. 2010 Jun 11;5(6):e11084
PubMed
2010 / 10.1074/jbc.M109.078360
Mandriota SJ, Buser R, Lesne L, Stouder C, Favaudon V, Maechler P, Bna F, Clment V, Regg C, Montesano R, Sappino AP. Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells. J. Bol. Chem, 2010 285:13092-106
PubMed
2009 / 10.1371/journal.pone.0004449
Alghisi GC, Ponsonnet L, Regg C. The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells. PLoS ONE 2009, 4: e4449
PubMed
2009 / 10.1002/pmic.200800359
Brembilla NC, Cohen-Salmon I, Weber J, Regg C, Quadroni M, Harshman K, Doucey MA. Profiling of T-cell receptor signaling complex assembly in human CD4 T-lymphocytes using RP protein arrays. Proteomics. 2009 Jan;9(2):299-309
PubMed
2008 / 10.1002/pmic.200800169
Baruthio F, Quadroni M, Regg C, Mariotti A. Proteomic analysis of membrane rafts of melanoma cells identifies protein patterns characteristic of the tumor progression stage. Proteomics. 2008 Nov;8(22):4733-47
PubMed
2008 / 10.1182/blood-2008-01-134486
Brembilla NC, Weber J, Rimoldi D, Pradervand S, Schtz F, Pantaleo G, Regg C, Quadroni M, Harshman K, Doucey MA. c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells. Blood. 2008 Aug 1;112(3):652-60
PubMed
2008 / 10.1007/s00418-008-0530-8
Lorusso G, Regg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem. Cell Biol. 2008, 130:1091-103
PubMed
2008 / 10.1158/0008-5472.CAN-08-0841
Monnier Y, Farmer P, Bieler G, Imaizumi N, Sengstag T, Alghisi GC, Stehle JC, Ciarloni L, Andrejevic-Blant S, Moeckli R, Mirimanoff RO, Goodman SL, Delorenzi M, Regg C. CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in pre-irradiated stroma. Cancer Res 2008, 68:7323-7331
PubMed
2008
Rossier-Pansier L, Baruthio F, Regg C, Mariotti A. Compartmentalization in membrane rafts defines a pool of N-cadherin associated with catenins and not engaged in cell-cell junctions in melanoma cells. J Cell Biochem. 2008 Feb 15;103(3):957-71
PubMed
2008
Regg C, Tissot JD, Farmer P, Mariotti A. Omics meets hypothesis-driven research. Partnership for innovative discoveries in vascular biology and angiogenesis. Thromb Haemost. 2008 Nov;100(5):738-46
PubMed
2008 / 10.1038/ncponc1150
Sessa C, Guibal A, Del Conte G, Regg C. Biomarkers of angiogenesis in the development of antiangiogenic therapies in oncology: tools or decorations? Nature Clin. Pract. Oncol. 2008, 5:378-91
PubMed
2007
Bieler G, Hasmim M, Monnier Y, Imaizumi N, Ameyar M, Bamat J, Ponsonnet L, Chouaib S, Grell M, Goodman SL, Lejeune F, Regg C. Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival. Oncogene. 2007 Aug 23;26(39):5722-32
PubMed
2007
Mariotti A, Perotti A, Sessa C, Regg C. N-cadherin as a therapeutic target in cancer. Expert Opin Investig Drugs. 2007 Apr;16(4):451-65
PubMed
2005
Zaric J, Regg C. Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation. J Biol Chem. 2005 Jan 14;280(2):1077-85
PubMed
2004
Regg C, Dormond O, Mariotti A. Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis. Biochim Biophys Acta. 2004 Mar 4;1654(1):51-67
PubMed
2003
Regg C, Mariotti A. Vascular integrins: pleiotropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell Mol Life Sci. 2003 Jun;60(6):1135-57
PubMed
2002
Dormond O, Bezzi M, Mariotti A, Regg C. Prostaglandin E2 promotes integrin αVβ3-mediated endothelial cell adhesion, Rac activation, and spreading through a cAMP/PKA-dependent effect. J. Biol. Chem. 2002, 277:45838-45846
PubMed
2001
Dormond O, Foletti A, Paroz C, Regg C. NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med. 2001 Sep;7(9):1041-7
PubMed
1998
Regg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ. Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFNgamma. Nature Med. 1998, 4:408-414 (with news and views article)
PubMed
1993
Palmer EL, Regg C, Ferrando R, Pytela R, Sheppard D. Sequence and tissue distribution of the integrin alpha9 subunit, a novel partner of beta1 that is widely expressed in epithelium and muscle. J. Cell Biol. 1993, 123:1289-1297
PubMed
1992
Regg C, Postigo AA, Sikorski EE, Butcher EC, Pytela R, Erle DJ. Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol. 1992 Apr;117(1):179-89
PubMed
1989
Regg C, Chiquet-Ehrismann R, Alkan SS. Tenascin, an extracellular matrix protein, exerts immunomodulatory activities. Proc. Natl. Acad. Sci. USA 1989, 86:7437-7441
PubMed