Vascular signaling Lab


Mariona Graupera – Group Leader
Pilar Villacampa – Postdoc - Juan de la Cierva fellow
Laia Muixi - Project manager - Phd ITN Marie Curie Network
Ana Angulo – Researcher
Ana M Figueiredo – VESSEL ITN Marie Curie Phd Student
Erika Monelli – VESSEL ITN Marie Curie Phd Student
Piotr Kobialka – Phd ITN Marie Curie Phd Student
Jasmina Zanoncello – Phd ITN Marie Curie Phd Student
Francisca Diniz – Erasmus Student
  • Description
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Our research is focused in understanding how signalling pathways regulate vessel growth (a process known as angiogenesis) during development and in disease.  Blood vessels are critical components of every organ, as they maintain tissue homeostasis by ensuring: vascular tone and barrier, blood coagulation, and transport of gases, nutrients, waste products and circulating cells. Endothelial cells line the inner surface of vessel tubes and are central to their biological function. In adequately perfused tissue – with nutrients and oxygen in abundance – endothelial cells are quiescent and form a streamlined inner vessel surface with tightly controlled barrier properties. When nutrients and oxygen are however limiting, endothelial cells become migratory and divide in order to form new vessel branches that re-vascularise the hypoxic tissue. To allow such adaptive behaviour, endothelial cells have evolved signalling mechanisms for efficient transitioning between long-term quiescence and periods of angiogenic growth.
A prototypic example of such a mechanism is the signalling network anchored by the PI3-kinases (PI3K). The PI3K family of proteins comprises eight catalytic members that are grouped into three classes. These lipid kinases act upstream in endothelial signalling transduction to control multiple facets of vascular development and function.
Over the last decade we have uncovered some critical aspects of how the PI3K signalling pathway controls angiogenesis in a pathophysiological context. Our major findings are: i) angiogenesis relays on PI3K signalling to make blood vessels during embryogenesis and tumourigenesis, ii) p110a is the only class I PI3K isoform which is essential during angiogenesis, iii) PTEN regulates endothelial cell quiescence downstream of Notch. From a pathological context, we have identified the PI3-kinase (PI3K) pathway as a critical target to treat three vascular diseases: i) solid tumour growth, where inhibition of PI3K results in non-productive angiogenesis, ii) venous malformation, in which we have reported the presence of activating PIK3CA (the gene encoding the p110a PI3K isoform) mutations in human patients and shown a complete regression of vascular lesions by inhibition of the PI3K pathway in a mouse model of this disease, and iii) arteriovenous malformations mediated by loss of Activin receptor-like kinase 1 expression, which overactivates endothelial cells PI3K as a result and blocking this activation reverts the malformation.   
Currently, my laboratory continues investigating why endothelial cells are exquisitely regulated by the PI3K pathway and which are the downstream effectors of PI3K during vessel growth. To this end, we use mouse embryos, retinas, tumours, vascular malformation lesions and white adipose tissue as models to uncover our critical biological questions in combination with genetically-engineered mice (GEM) to model relevant molecular alterations.
Our lab is located in the Bellvitge Institute for Biomedical Research ( IDIBELL ) in Barcelona, and is affiliated with the Catalan Institute of Oncology within the Program Against Cancer Therapeutic Resistance (ProCURE). We receive funding from MINECO, European Union's Horizon 2020 research and innovation programme, AGAUR, Fundació Bancària la Caixa.
www.ncbi.nlm.nih.gov/pubmed/?term=Graupera+M​
2016
  • Mateo, F., Arenas, E.J., Aguilar, H., Serra-Musach, J., de Garibay, G.R., Boni, J., Maicas, M., Du, S., Iorio, F., Herranz-Ors, C.,... Graupera, M... Pujana MA. .et al. (2016). Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene. 2016 Dec 19. doi: 10.1038/onc.2016.427..
 
  • Ola R , Dubrac A, Han J, Fang JS, Zhang F, Larrivée B+, Lee M, Angulo-Urarte A, Genet G, Hirschi KK, Sessa WC, Vinals F, Graupera M, Yan M, Young LW Oh SP, Eichmann A. PI3 Kinase inhibition improves vascular malformations in mouse models of hereditary hemorrhagic telangiectasia type 2. Nat Commun. 2016 Nov 29;7:13650. doi: 10.1038/ncomms13650.
 
  • Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Sep 21.
 
  • Alsina-Sanchis E, Figueras A, Lahiguera Á, Vidal A, Casanovas O, Graupera M, Villanueva A, Viñals F. The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels. Int J Cancer. 2016 Jun 14. doi: 10.1002/ijc.30233.
 
  • Soler A, Figueiredo AM, Castel P, Martin L, Angulo-Urate A, Milà-Gusach M, Viñals F, Baselga J, Casanovas O, Graupera M. Therapeutic benefit of restricted p110a inhibition of PI3-kinase isoform in pancreatic neuroendocrine tumors. Clin Cancer Res. 2016 May 25. pii: clincanres.3051.2015
 
  • Torrado V, Valcarcel-Jimenez L, Cortazar, AR, Liu X, Urosevic J, Castillo-Martin M, Fernández-Ruiz S, Morciano G, Caro-Maldonado A, Guiu M, Zúñiga-Garcia P, Graupera M, Pandya P, Lorente M, Martín-Martín N, Sutherland JD, Bozal L, Zabala-Letona A, Arruabarrena-Aristorena A, Embade N, Ugalde-Olano A, Lacasa-Viscasillas I, Loizaga-Iriarte A, Unda-Uraiz M, Schultz N, Aransay AM, Sanz-Moreno V, Barrio R, Velasco G, Cordon-Cardo C, Gomis RR, Losasale JW, Carracedo A. A metabolic co-regulator bio-informatics screen reveals that PGC1a suppresses prostate cancer metastasis. Nat Cell Biol. 2016 May 23. doi: 10.1038/ncb3357.
 
  • Jimenez-Valerio G, Martinez-Lozano M, Bassani N, Vidal A, Ochoa-de-Olza M, Suarez C, Garcia-del-Muro X, Capdevila JC, Viñals F, Graupera M, Indraccolo S, Casanovas O. Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients. Cell Rep. 2016 Apr 27. pii: S2211-1247(16)30428-4. doi: 10.1016/j.celrep.2016.04.015 
 
  • Gámez B, Rodríguez-Carballo E, Graupera M, Rosa JL & Ventura F.  Class I PI-3-Kinase signaling is critical for bone formation through regulation of SMAD1 activity in osreoblasts. Journal of Bone and Mineral Research. J Bone Miner Res. 2016 Feb 20. doi: 10.1002/jbmr.2819
 
  • Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker V, Chivite I, Milà-Guasch M, Pearce W, Solomon I, Angulo-Urarte A, Figueiredo AM, Dewhurst RE, Knox RG, Clark GR, Scudamore CL, Badar A, Kalber TL, Foster J, Stuckey DJ, David A, Phillips WA, Lythgoe MF, Wilson V, Semple RK, Sebire NJ, Kinsler VA, Graupera M¥, & Vanhaesebroeck B¥. Somatic Activating Mutations in Pik3ca Cause Sporadic Venous Malformations in Mice and Human. Sci Transl Med. 2016 Mar 30;8(332):332ra43
 
2015
  • Calderone, Mejias M, Bava F, Angulo-Urarte A, Graupera M, Navarro P, Bosch J, Fernandez M, Mendez R. Sequential Functions of CPEB1 and CPEB4 Regulate Pathologic Expression of Vascular Endothelial Growth Factor and Angiogenesis in Chronic Liver Disease. Gastroenterology. 2015 Nov 25. pii: S0016-5085(15)01720-5.
 
  • Serra H, Chivite I, Angulo-Urarte A, Soler A, Sutherland JD, Arruabarrena-Aristorena A, Ragab A, Lim R, Malumbres M, Fruttiger M, Potente M, Serrano M, Fabra À, Viñals F, Casanovas O, Pandolfi PP, Bigas A, Carracedo A, Gerhardt H, Graupera M*. PTEN mediates Notch-dependent stalk cell arrest in angiogenesis. Nat Commun. 2015 Jul 31;6:7935. doi: 10.1038/ncomms8935.
 
  • Guillermet-Guibert J, Smith LB, Halet G, Whitehead MA, Pearce W, Rebourcet D, León K, Crépieux P, Nock G, Strömstedt M, Enerback M, Chelala C, Graupera M, Carroll J, Cosulich S, Saunders PT, Huhtaniemi I, Vanhaesebroeck B. Novel Role for p110β PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells. PLoS Genet. 2015 Jul 1;11(7):e1005304. doi: 10.1371/journal.pgen.1005304.
 
  • Stanczuk L, Martinez-Corral I, Ulvmar MH, Zhang Y, Laviña B, Fruttiger M, Adams RH, Saur D, Betsholtz C, Ortega S, Alitalo K, Graupera M, Mäkinen T. cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels. Cell Rep. 2015 Mar 10. pii: S2211-1247(15)00172-2. doi: 10.1016/j.celrep.2015.02.026.
 
  • S Soler A, Angulo-Urarte A, Graupera M*. PI3K at the crossroads of tumour angiogenesis signalling pathways. Molecular & Cellular Oncology. 2015 Volume 2, Issue 2
 
2014
  • Juliachs M, Muñoz C, Moutinho CA, Vidal A, Condom E, Esteller M, Graupera M, Casanovas O, Germà JR, Villanueva A, Viñals F. The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors. Clin Cancer Res. 2014 Feb 1;20(3):658-67. doi: 10.1158/1078-0432.CCR-13-1131
 
2013
  • Soler A, Serra H, Pearce W, Angulo A, Guillermet-Guibert J, Friedman LS, Viñals F, Gerhardt H, Casanovas O, Graupera M¥,* Vanhaesebroeck B¥.  Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis. J Exp Med. 2013 Sep 23;210(10):1937-45
 
  • Juliachs M, Vidal A, Del Muro XG, Piulats JM, Condom E, Casanovas O, Graupera M, Germà JR, Villanueva A, Viñals F. Effectivity of pazopanib treatment in orthotopic models of human testicular germ cell tumors. BMC Cancer. 2013 Aug 10;13:382. doi: 10.1186/1471-2407-13-382.
 
  • Vives M, Ginestà MM, Gracova K, Graupera M, Casanovas O, Capellà G, Serrano T, Laquente B, Viñals F. Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. Int J Cancer. 2013 Nov 15;133(10):2464-72. doi: 10.1002/ijc.28259. Epub 2013 Jun 4.
 
  • Graupera M*, Potente M. Regulation of angiogenesis by PI3K signaling networks. Exp Cell Res. May 15;319(9):1348-55.
 
  • Juliachs M, Castillo-Ávila W, Vidal A, Piulats JM, Garcia Del Muro X, Condom E, Hernández-Losa J, Teixidó C, Pandiella A, Graupera M, Casanovas O, Germà JR, Villanueva A, Viñals F. ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor. Int J Cancer. 2013 Jul;133(1):235-46. doi: 10.1002/ijc.28009. Epub 2013 Feb 12.
 
2012

  • Fernández-Martín L, Marcos-Ramiro B, Bigarella CL, Graupera M, Cain RJ, Reglero-Real N, Jiménez A, Cernuda-Morollón E, Correas I, Cox S, Ridley AJ, Millán J.   Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):e90-102. doi: 10.1161/ATVBAHA.112.252080. Epub 2012 Jun 21.
 
2011

  • Stenzel D, Lundkvist A, Sauvaget D, Busse M, Graupera M, van der Flier A, Wijelath ES, Murray J, Sobel M, Costell M, Takahashi S, Fässler R, Yamaguchi Y, Gutmann DH, Hynes RO, Gerhardt H. Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis. Development. 2011 Oct;138(20):4451-63. doi: 10.1242/dev.071381.
 
2010

  • Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010 May;11(5):329
 
2008

  • Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AJ, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature. 2008. May 29;453(7195):662





















FUNDING

Project Title: A Pilot Project for Personalized Cancer Medicine: Oncoprofile (PIE13/00022)
Funding Source: Spanish Ministry of Health
Amount: TOTAL: 605.000€. For MG only: 20.000€
Period: 2014-2016 extended until mid 2017
Role of the PI: Beneficiary (Coordinated by Manel Esteller)
 
Project Title: Quiescencia de las células endoteliales mediada por PTEN como una neva terapia vascular anti-tumoral (SAF2014-599950-P)
Funding Source: Spanish Ministry of Economy and Science
Amount: 133.100€
Period: 2015-2017
Role of the PI: Beneficiary
 
Project Title: Deciphering PI3K biology in health and disease (Phd-675392)
Funding Source: H2020-MSCA-ITN-2015
Amount: TOTAL: 3.800.000€. For MG only: 776.545€
Period: Nov 2015- Oct 2019
Role of the PI: COORDINATOR
 
Project Title. Identification of the metabolic and signaling interplay underlying the acquisition of invasive and metastatic properties in PCa as a mean to define novel therapeutic targets and stratification markers. (CIBER CANCER –CB16/12/00445)
Funding Source. Ministerio de Sanidad
Amount: not disclosed yet
Period: 2017-2018
Role of the PI: Beneficiary
 
Project Title. Phosphoinositide 3-kinase Signalling in Oncogenic Vascular Malformations.
Funding Source. Fundació Bancària Caixa d’Estalvis i Pensions de Barcelona, ”la Caixa”
Amount: 255.535€
Period: 2017-2019
Role of the PI: Beneficiary

To inquire about open positions please contact:

​Dr. Mariona Graupera
Program Against Cancer Therapeutic Resistance, ProCURE
Catalan Institute of Oncology
Bellvitge Biomedical Research Institute, IDIBELL
3 floor, LRT1, Hospital Duran i Reynals
Gran Via 199-203, 08907 L’Hospitalet de Llobregat
​