ICO - German Trias i Pujol
Josep Carreras Leukaemia Research Institute
Can Ruti Campus - Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona
Our research is devoted to study the biology of the endothelium and its role in disease towards the development of therapeutic strategies to target this compartment. Specifically, we aim to untackel the fundamental insigths of vessel growth and function in developmental setting as well as to identify the pathological contexts in which the vasculature plays a critical role either intrinsically, as in vascular anomalies, or extrinsically as in cancer.
Blood vessels are crucial components of every organ, as they maintain tissue homeostasis by ensuring: (i) transport of gases, nutrients, waste products and circulating cells, (ii) blood coagulation, and (iii) vascular tone and barrier. The endothelium lines the lumen of blood vessels and regulates the dynamic passage of materials and cells, whereas mural cells adhere to the abluminal surface of the endothelium and regulate vessel growth, permability and function. Both excessive and insufficient vascular network is deleterious for organisms and lead to a broad spectrum of pathologies.
The overall aim of the Graupera lab is to understand the mechanisms that regulate the vasculature in development, homeostasis and disease. Most of our research has focused on the the endothelium that plays an active role in important physiological processes and diseases such congenital disorders, obesity and cancer.
Over the past decade, we have taken advantage of the PI3K pathway as a paradigm to understand how intracellular roads regulate vessel morphogenesis, and how this knowledge can be translated into therapeutic opportunities for diseases with aberrant angiogenesis.
For our research, our lab develops unique animal models including, established cell lines, and patient-derived samples. We apply a holistic approach utilising state-of-the-art techniques as high-throughput analysis, next-generation sequencing, single cell RNA sequencing, phospho/proteomics, and high-resolution imaging. Our lab closely collaborates with clinicians to translate our research into the clinic at both the diagnostic and therapeutic levels.
The Graupera lab is devoted to 5 main research lines:
1. Insights on developmental vessel growth and function.
2. Understanding oncoproteins-related developmental disorders.
3. To study tumour-stroma interaction.
4. Identify vascular therapies to treat metabolic disorders.
5. To study endothelial and hematopoietic cell interface
Image 1: Clonal expansion in endothelial tumors
2020 - EVBO Lecture Award for 21st IVBM, Seoul, Korea September 2020.
2020 - Ayudas Fundación BBVA a Equipos de Investigación Científica en Biomedicina 2019
2019 - Best female Scientist of CIBERONC
2018 - Beca Salvador de Madariaga – Estancia de movilidad de profesores e investigadores españoles en centros extranjeros.
2017 - Beca Leonardo Fundación BBVA
2013 - Successfully evaluated for the I3 program (“Ramon y Cajal” follow up program)
2008 - Reintegration Fellowship: “Ramon y Cajal” young research investigator tenure track position from the Spanish Ministry of Science and Education
2006 - Cancer Research-UK fellowship
2004 - EMBO Post-doctoral Fellowship (LTF364-2004)
Show all publications
PI3Kb-regulated pericyte maturation governs vascular remodelingCirculation. 2020 Aug 18;142(7):688-704 , .
Background: Pericytes regulate vessel stabilization and function, and their loss is associated with diseases such as diabetic retinopathy or cancer. Despite their physiological importance, pericyte function and molecular regulation during angiogenesis remain poorly understood.
Methods: To decipher the transcriptomic programs of pericytes during angiogenesis, we crossed Pdgfrb(BAC)-CreERT2 mice into RiboTagflox/flox mice. Pericyte morphological changes were assessed in mural cell-specific R26-mTmG reporter mice, in which low doses of tamoxifen allowed labeling of single-cell pericytes at high resolution. To study the role of phosphoinositide 3-kinase (PI3K) signaling in pericyte biology during angiogenesis, we used genetic mouse models that allow selective inactivation of PI3Kα and PI3Kβ isoforms and their negative regulator phosphate and tensin homolog deleted on chromosome 10 (PTEN) in mural cells.
Results: At the onset of angiogenesis, pericytes exhibit molecular traits of cell proliferation and activated PI3K signaling, whereas during vascular remodeling, pericytes upregulate genes involved in mature pericyte cell function, together with a remarkable decrease in PI3K signaling. Immature pericytes showed stellate shape and high proliferation, and mature pericytes were quiescent and elongated. Unexpectedly, we demonstrate that PI3Kβ, but not PI3Kα, regulates pericyte proliferation and maturation during vessel formation. Genetic PI3Kβ inactivation in pericytes triggered early pericyte maturation. Conversely, unleashing PI3K signaling by means of PTEN deletion delayed pericyte maturation. Pericyte maturation was necessary to undergo vessel remodeling during angiogenesis.
Conclusions: Our results identify new molecular and morphological traits associated with pericyte maturation and uncover PI3Kβ activity as a checkpoint to ensure appropriate vessel formation. In turn, our results may open new therapeutic opportunities to regulate angiogenesis in pathological processes through the manipulation of pericyte PI3Kβ activity.Més informació
Developmental and tumour angiogenesis requires the mitochondria-shaping protein Opa1Cell Metab. 2020 May 5;31(5):987-1003.e8 , .
While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis.Més informació
Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractilityNat Commun. 2018 Nov 16;9(1):4826 , .
Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kα regulates endothelial cell rearrangements using a combination of a PI3Kα-selective inhibitor and endothelial-specific genetic deletion to abrogate PI3Kα activity during vessel development. Quantitative phosphoproteomics together with detailed cell biology analyses in vivo and in vitro reveal that PI3K signalling prevents NUAK1-dependent phosphorylation of the myosin phosphatase targeting-1 (MYPT1) protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility. Decreased PI3K activity enhances actomyosin contractility and impairs junctional remodelling and stabilization. This leads to overstretched endothelial cells that fail to anastomose properly and form aberrant superimposed layers within the vasculature. Our findings define the PI3K/NUAK1/MYPT1/MLCP axis as a critical pathway to regulate actomyosin contractility in endothelial cells, supporting vascular patterning and expansion through the control of cell rearrangement.Més informació
Somatic Activating Mutations in Pik3ca Cause Sporadic Venous Malformations in Mice and HumanSci Transl Med. 2016 Mar 30;8(332):332ra43 , .
Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.Més informació
The metabolic co-regulator PGC1α suppresses prostate cancer metastasisNat Cell Biol. 2016 Jun;18(6):645-656 , .
Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.Més informació