Director, Preclinical Research Program
“We strive to advance prediction science against cancer by developing xenograft models to study tumorigenesis, elucidate the cross-talk between tumor cells and the microenvironment, and evaluate the efficacy of novel therapies. By upping the tempo in unmasking mutations and mechanisms of resistance to current anti-cancer medicines we are ultimately contributing to improved outcomes for patients.”
› Violeta Serra
› Cristina Cruz
› Jordi Rodón
› Alba Llop-Guevara
› Marta Palafox
› Marta Castroviejo-Bermejo
› Albert Gris-Oliver
› Mònica Sánchez-Guixé
› Judit Grueso
› Marta Guzmán
› Olga Rodríguez
VHIO’s Experimental Therapeutics Group conducts bench-to-bedside preclinical research in breast cancer to advance insights into targeted-therapeutics response biomarkers. We have advanced the field of PI3K inhibitor resistance by firstly evidencing that an adaptive response activating the MEK/ERK pathway through receptor tyrosine kinase upregulation bypasses the PI3K-survival pathway and mediates resistance to PI3K inhibitor. Secondly, we have identified that RSK, a MEK/ERK downstream kinase limits the activity of dual PI3K/mTOR inhibitors partly through the attenuation of apoptotic response and upregulation of protein translation.
Our group has also contributed to identifying PI3K-pathway activation downstream of PI3K, via upregulation of mTORC1, as a mechanism of resistance to PI3K inhibitors. To advance our understanding of the novel therapeutic strategies in breast cancer, we are exploring the mode of action and mechanisms of resistance of CDK4/6 inhibitors (drug combinations with PI3K inhibitors and hormone therapy) in endocrine-resistant breast tumors. Using clinically relevant patient-derived tumor xenografts we have established that loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 or CCND1-amplification, is associated with lack of response to CDK4/6 blockade in estrogen receptor positive breast cancer PDX. The addition of a PI3Kalpha inhibitor results in improved and prolonged disease control in all experimental models analyzed.
Encouraged by the early success of DNA damage repair inhibitors in germline BRCA1/2 tumors we have initiated a project aimed at identifying response biomarkers of PARP inhibitors (PARPi) and DNA binding agents including PM01183, a novel derivative of trabectedine, in homologous recombination (HR) DNA repair deficient tumors. Our studies underpin the capacity of germline BRCA mutant tumors to recover HR functionality and develop resistance to PARPi. PM01183 is however active in most PARPi resistant tumors, as well as PARPi combinations that bypass cell cycle checkpoints such as WEE1 inhibitors.
In short, our group has significantly improved the understanding of the mode of action of novel targeted therapies, identified new response biomarkers, and demonstrated the efficacy of hypothesis-based drug combinations.
Figure: RAD51 and DNA repair by homologous recombination functionality. The homologous recombination (HR) protein RAD51 is recruited to finalize the repair of double strand breaks in HR-competent cells. This biomarker enables the identification of breast tumors that lack HR-functionality and therefore sensitive to PARP inhibitors, both in the BRCA1/2-germline and in the somatic context.
Herrera-Abreu M, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortés J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC, Serra V. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor positive breast cancer. Cancer Res. 2016 Apr 15;76(8):2301-13.
Bruna A, Rueda OM, Greenwood W, Batra AS, Callari M, Batra RN, Pogrebniak K, Sandoval J, Cassidy JW, Tufegdzic-Vidakovic A, Sammut SJ, Jones L, Provenzano E, Baird R, Eirew P, Hadfield J, Eldridge M, McLaren-Douglas A, Barthorpe A, Lightfoot H, O'Connor MJ, Gray J, Cortes J, Baselga J, Marangoni E, Welm AL, Aparicio S, Serra V, Garnett MJ, Caldas C. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds. Cell. 2016 Sep 22;167(1):260-274.e22.
Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, Plumb DA, Zakka L, Gazinska P, Liccardi G, Meier P, Gris-Oliver A, Cheang MCU, Perdrix-Rosell A, Shafat M, Noël E, Patel N, McEachern K, Scaltriti M, Castel P, Noor F, Buus R, Mathew S, Watkins J, Serra V, Marra P, Grigoriadis A & Tutt AN. PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat Med. 2016 Nov;22(11):1303-1313.
Drost R, Dhillon KK, van der Gulden H, van der Heijden I, Brandsma I, Cruz C, Chondronasiou D, Castroviejo-Bermejo M, Boon U, Schut E, van der Burg E, Wientjens E, Pieterse M, Klijn C, Klarenbeek S, Loayza-Puch F, Elkon R, van Deemter L, Rottenberg S, van de Ven M, Dekkers DH, Demmers JA, van Gent DC, Agami R, Balmaña J, Serra V, Taniguchi T, Bouwman P, Jonkers J. BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J Clin Invest. 2016 Aug 1;126(8):2903-18.
› Joaquín Arribas
› Cristina Bernadó
› César Serrano
› Cristina Bernadó
› Beatriz Morancho
› Mercedes Nadal
› Bhavna Rani
› Verónica Rodilla
› Rita Casas
› Faiz Bilal
› Irene Rius
› Rocio Vicario
› Junjie Zhang
› Marta Escorihuela
› Antoni Luque
› David Olivares
› Ismael Varela
Our group is dedicated to studying tumor progression and mechanisms of resistance to therapy in HER2-positive breast cancer as well as the development of novel immunotherapy strategies against this tumor subtype.
We have previously shown that constitutively activated HER2 leads to premature senescence. These senescent cells remain metabolically active and display a remarkable secretory phenotype. We deeply analyzed this secretome and evidenced that it contributes to the prometastatic effect of HER2-induced senescent cells.
We extended our studies to naturally-occurring senescent cells in HER2-positive tumors. In this scenario, senescent cells contribute to tumor growth by secreting cytokines that are required for non-senescent cells to proliferate. We identified IL-6 as one of the main contributors and established that the autocrine production of this element by naturally occurring senescent cells promotes growth of HER2-positive tumors.
Throughout 2016 our group has also evaluated the efficacy of anti-IL-6 therapies using breast cancer patient derived xenografts (PDXs). Results indicate that only tumors in which activation of STAT3 depends on IL-6, respond to the blocking antibodies, suggesting the necessary development of functional assays to determine the dependence of STAT3 activation on IL-6, and identify responsive tumors.
Most recently, we have focused on developing tools to better model anti-tumor immunotherapy strategies. The development of humanized PDX models (Hu PDXs), in which the human immune system is established in PDX-bearing immunodeficient mice, has proven a successful approach. We are currently using these models to preclinically validate the efficacy of T cell bispecific antibodies (TCBs).
In addition, our group has been setting up a new line of research focused on pancreatic cancer. In close collaboration with VHIO’s Gastrointestinal & Endocrine Tumors Group, led by Josep Tabernero, we are expanding our research to explore resistance mechanisms implicated in the response to targeted therapies against this tumor type.
We are extremely grateful to both the Spanish Association Against Cancer (AECC), and the Breast Cancer Research Foundation (BCRF), for their continued funding of our research. Lastly, after several years' coordination of the Breast Cancer Program of the Red Territorial de Investigación Cooperativa en Cáncer (RTICC), supported by the Instituto de Salud Carlos III (ISCIII), I am honored to have recently been appointed as Scientific Director of the virtual Centro de Investigación Biomédica en Red (CIBER-ONC: Center for the Biomedical Research Network in Oncology). This new network is comprised of several of the most active cancer research groups across Spain. We work in close connectivity to collectively deliver on complex projects requiring the collaboration and expertise of multiple groups.
Figure: Strategies to generate humanized PDXs. Nature Reviews Cancer (2017) doi:10.1038/nrc.2016.140.
Morancho B, Zacarías-Fluck M, Esgueva A, Bernadó-Morales C, Di Cosimo S, Prat A, Cortés J, Arribas J, Rubio IT. Modeling anti-IL-6 therapy using breast cancer patient-derived xenografts. Oncotarget. 2016 Oct 18;7(42):67956-67965.
Serra-Musach J, Mateo F, Capdevila-Busquets E, de Garibay GR, Zhang X, Guha R, Thomas CJ, Grueso J, Villanueva A, Jaeger S, Heyn H, Vizoso M, Pérez H, Cordero A, Gonzalez-Suarez E, Esteller M, Moreno-Bueno G, Tjärnberg A, Lázaro C, Serra V, Arribas J, Benson M, Gustafsson M, Ferrer M, Aloy P, Pujana MÀ. Cancer network activity associated with therapeutic response and synergism. Genome Med. 2016 Aug 24;8(1):88.
Hergueta-Redondo M, Sarrio D, Molina-Crespo Á, Vicario R, Bernadó-Morales C, Martínez L, Rojo-Sebastián A, Serra-Musach J, Mota A, Martínez-Ramírez Á, Castilla MÁ, González-Martin A, Pernas S, Cano A, Cortes J, Nuciforo PG, Peg V, Palacios J, Pujana MÁ, Arribas J, Moreno-Bueno G. Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer. Oncotarget. 2016 Aug 30;7(35):56295-56308.
Nuciforo, P., Thyparambil, S., Aura, C., Garrido-Castro, A., Marta Vilaro, M., Peg, V., Jimenez, J., Hoos, W., Burrows, J., Todd Hembrough, T., Ferreres, J. C., Perez-Garcia, J., Arribas, J., Cortes, J., and Scaltriti, M. High HER2 protein levels correlate with increased overall survival in breast cancer patients treated with anti-HER2 therapy. Mol. Oncol. 2016 Jan;10(1):138-47.
› Laura Soucek
› Jonathan Whitfield
› Marie-Eve Beaulieu
› Silvia Casacuberta
› Mariano F. Zacarias
› Toni Jauset González
› Sandra Martínez
› Daniel Massó Vallés
› Virginia Castillo
› Laia Foradada
› Érika Serrano del Pozo
Visiting Postdoctoral Scholar
› Roberta Laranga
Our group focuses on the pleiotropic and ubiquitous Myc oncoprotein, whose deregulation is implicated in almost all human cancers. The technical challenges of targeting nuclear transcription factors such as Myc – and the concern regarding potential side effects – had until recently precluded any preclinical validation of Myc inhibition as a possible therapeutic approach. However, over the past few years, we have demonstrated in several mouse models that Myc inhibition has a dramatic therapeutic impact across several tumor types, with very mild and reversible side effects in normal tissue.
Encouraged by our results in mice, we are now interested in developing viable, nontoxic pharmacological options for Myc targeting in the clinic. To do so, we have created a spin-off company, Peptomyc S.L., for the development of Myc-inhibiting peptides for cancer therapy, and we are validating our new therapeutic strategy in notoriously difficult to treat cancers that are currently resistant to standard therapies and are in dire need of new therapeutic options (i.e. KRas-driven Non-Small Cell Lung Cancer, glioblastoma, and metastatic triple negative breast cancer).
In recognition of research of excellence, Laura's laboratory has been awarded numerous grants since its inception. This year she has received a prestigious European Research Council (ERC) Proof-of-Concept grant within the framework of the EU's Horizon 2020 Program, a grant from the Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) for a FIS - Fondo de Investigación en Salud (Health Research Fund) project, and a grant from the Spanish Ministry of Economy, Industry and Competitiveness within the Retos de Colaboración program.
Figure: Laura Soucek’s laboratory is pre-clinically validating Myc inhibition as a therapeutic strategy in different types of cancer. To do so, among other strategies, they are using Omomyc, the best Myc inhibitor known to date, and Omomyc-derived peptides.
Massó-Vallés D, Jauset T, Soucek L. Ibrutinib repurposing: from B cell malignancies to solid tumors. Oncoscience. 2016 Jun 10;3(5-6):147-8.
Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, Kohno T, Perucho M, Soucek L, Yokota J. Growth Suppression by MYC Inhibition in Small Cell Lung Cancer Cells with TP53 and RB1 Inactivation. Oncotarget. 2016 May 24;7(21):31014-28.
› Josep Villanueva
› Mercè Juliachs
› Juan Manuel Duran
› Olga Méndez
› Nathalie Meo-Evoli
› Mireia Pujals
› Ana Matres
› Candida Salvans
Tumor cell communication with its microenvironment plays an important role in tumor initiation and progression. Tumor cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is crucial for the development of primary and metastatic tumors.
Our main aim is to characterize the mechanisms adopted by cancer cells to communicate both amongst themselves as well as with their microenvironment during tumorigenesis. We then exploit these findings to contribute to the advancement of biomarker and drug target discovery. Our group’s working hypothesis is that cellular signaling pathways undergo alteration during tumorigenesis and that these changes translate in differential protein secretion, which can also potentially be explored to identify secreted markers. In addition, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to fundamental stages implicated in cancer initiation and progression, thus representing potential therapeutic targets.
The methodological focus of our group centers on profiling the secreted sub-proteome (‘secretome’) of cells by quantitative mass spectrometry. Most secreted proteins contain a signal peptide that directs their sorting to the extracellular space through the endoplasmic reticulum (ER)–Golgi secretory pathway. One of the most striking observations when secretome profiles are carefully produced and analyzed, however, is that they contain hundreds of theoretical intracellular proteins. Recent reports evidence intracellular proteins with alternative extracellular functions, suggesting that new protein functions associated with alternative subcellular localizations might be implicated in tumorigenesis. Considering this novel concept, in the context of therapeutics and tumor invasion, we hypothesize that the characterization of non-classical protein secretion could lead to novel therapies against cancer.
The cancer secretome contains classical and non-classical secreted proteins that tumor cells use as molecular messaging to communicate with each other and their microenvironment during tumorigenesis. Our principal goal is to characterize the mechanisms adopted by cancer cells which enable this cross-talk, and exploit our findings in order to accelerate biomarker and drug target discovery.
Figure: Proteins change their sub-cellular localization in breast cancer. IHC analysis of secretome proteins in both normal and cancer breast tissue obtained from Protein Atlas database. In each case, one normal breast tissue and three different breast tumors are shown. (Top panel) IHC analysis of known extracellular proteins (CTGF and Cyr61) showing a clear cytoplasmic/membranous staining in both normal and breast cancer. (Bottom panel) IHC analysis of the two secretome proteins: Ssb and Thrap3, both classified as nuclear by Gene Ontology. In this case, these theoretically nuclear proteins show a clear cytoplasmic staining in some tumors but not in normal tissue, which is compatible with a change in subcellular localization in breast cancer.