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ERC Advanced Grant (ERC-AdG)

Título/Title: CELLPLASTICITY: New Frontiers in Cellular Reprogramming: Exploiting Cellular Plasticity
Ref.: 669622
Investigador Principal/Principal Investigator: Serrano Marugán, Manuel
Fecha Inicio/Starting Date: 01/10/2015
Fecha Fin/Ending Date: 30/04/2017
Presupuesto/Budget: 2.488.850,00 €
Comentarios/Comments: HORIZON 2020 (2014-2020)

Resumen/Summary

Our research group has worked over the years at the interface between cancer and ageing, with a strong emphasis on mouse models. More recently, we became interested in cellular reprogramming because we hypothesized that understanding cellular plasticity could yield new insights into cancer and ageing. Indeed, during the previous ERC Advanced Grant, we made relevant contributions to the fields of cellular reprogramming (Nature 2013), cellular senescence (Cell 2013), cancer (Cancer Cell 2012), and ageing (Cell Metabolism 2012). Now, we take advantage of our diverse background and integrate the above processes. Our unifying hypothesis is that cellular plasticity lies at the basis of tissue regeneration (“adaptive cellular plasticity”), as well as at the origin of cancer (“maladaptive gain of cellular plasticity”) and ageing (“maladaptive loss of cellular plasticity”). A key experimental system will be our “reprogrammable mice” (with inducible expression of the four Yamanaka factors), which we regard as a tool to induce cellular plasticity in vivo. The project is divided as follows: Objective #1 – Cellular plasticity and cancer: role of tumour suppressors in in vivo de-differentiation and reprogramming / impact of transient de-differentiation on tumour initiation / lineage tracing of Oct4 to determine whether a transient pluripotent-state occurs during cancer. Objective #2 – Cellular plasticity in tissue regeneration and ageing: impact of transient de-differentiation on tissue regeneration / contribution of the damage-induced microenvironment to tissue regeneration / impact of transient de-differentiation on ageing. Objective #3: New frontiers in cellular plasticity: chemical manipulation of cellular plasticity in vivo / new states of pluripotency / characterization of in vivo induced pluripotency and its unique properties. We anticipate that the completion of this project will yield new fundamental insights into cancer, regeneration and ageing.

ERC Advanced Grant (ERC-AdG)

Título/Title: THERACAN: Novel therapeutic strategies to treat pancreatic and lung cancer
Ref.: 695566
Investigador Principal/Principal Investigator: Barbacid Montalbán, Mariano
Fecha Inicio/Starting Date: 01/01/2017
Fecha Fin/Ending Date: 31/12/2021
Presupuesto/Budget: 2.499.500,00 €
Comentarios/Comments: HORIZON 2020 (2014-2020)

Resumen/Summary

This proposal is aimed at identifying and functionally validating targets with potential therapeutic value to devise novel strategies to treat two human cancers with unacceptable low survival rates and unmet medical needs: pancreatic ductal adenocarcinoma and K-RAS mutant lung adenocarcinoma. Although these tumor types have distinct pathological and clinical manifestations, they are both driven by K-RAS mutations. Hence, we expect that the proposed studies will generate synergies to accelerate the outcome of the expected results. In the first part of the proposal, we will identify those genes activated in the cancer initiating cells responsible for the onset of pancreatic and lung tumors. We reasoned that genes implicated in the initial stages of tumor development will be maintained during tumor evolution and not be affected by the intra-tumoral heterogeneity generated during tumor progression. We also propose to identify and validate genes capable of reprogramming the desmoplasic stroma characteristic of pancreatic tumors to hamper its pro-tumoral effects. Likewise, we intend to define the molecular events that control senescence, a naturally occurring process that serves as a barrier to tumor development. In the second part of the project, we will interrogate the role of known targets with suspected therapeutic value in tumor progression using a new generation of GEM tumor models that allow the temporal separation of tumor development from target ablation or inactivation. These studies will make it possible to design combination therapies capable of effectively eradicate advanced tumors. The last section of this proposal focuses on the pharmacological validation of these combination therapies using best-in-class inhibitors in state-of-the-art preclinical trial platforms based on GEM and PDX tumor models. The results derived from these studies will guide the design of new clinical trials that should have a positive impact in the treatment of these deadly diseases.

ERC Consolidator Grant (ERC-CoG)

Título/Title: RSHEALTH: Investigating the causes and consequences of replication stress in mammalian health
Ref.: 617840
Investigador Principal/Principal Investigator: Fernández-Capetillo, Oscar
Fecha Inicio/Starting Date: 01/03/2014
Fecha Fin/Ending Date: 28/02/2019
Presupuesto/Budget: 1.997.819,05 €
Comentarios/Comments: VII FRAMEWORK PROGRAMME (2007-2013)

Resumen/Summary

DNA damage (DD) is the cause of several diseases, including cancer, and it is also linked to the organ decline that arises in ageing. Yet, the contribution of different sources of DD to these processes is not understood. Sources of DD such as chromosome breaks, eroded telomeres or oxidative stress are been heavily investigated. For establishing my group, I decided to focus on a source of DD that arises every time a cell replicates its DNA, and which is known as replication stress (RS). In short, RS stands for the excessive accumulation of single-stranded DNA at replication forks that, due to its recombinogenic nature, can initiate genomic rearrangements. Consistently, RS is now known to be a key source of genomic instability in human tumors. In mammalian cells, a signalling cascade initiated by ATR and Chk1 kinases suppresses RS. Unfortunately, the essential nature of these kinases significantly limited the study of the RS-response in mammals. In the initial years of our lab we have developed several tools that facilitate the study of RS in mammals. These include a cellular system where ATR can be activated at will, potent and selective ATR inhibitors, and mice with reduced or increased levels of ATR and Chk1 kinases. These tools have allowed us to start exploring how RS impacts on cancer and ageing, as well as to investigate the potential of targeting ATR for cancer therapy. Yet, the field of RS is still poorly developed, and many basic questions are still in the need of answers.

This application outlines a plan for our research in the next five years, and explains how I propose to investigate RS at molecular, cellular and animal levels. Whereas I plan to capitalize on the tools (published and unpublished) that we have generated within the last few years, I also propose several innovative strategies for the study of the RS-response in mammals. This grant would allow us to consolidate our still young group as a solid laboratory for the study of RS in mammals.

ERC Consolidator Grant (ERC-CoG)

Título/Title: PLEIO-RANK: Pleiotropic treatment of cancer: RANK inhibitors targeting cancer stem cells and immunity
Ref.: 682935
Investigador Principal/Principal Investigator: González Suárez, Eva
Fecha Inicio/Starting Date: 01/08/2019
Fecha Fin/Ending Date: 30/09/2021
Presupuesto/Budget: 1.999.960,00 €
Comentarios/Comments: HORIZON 2020 (2014-2020). Transferred to CNIO.

Resumen/Summary

PLEIO-RANK has been designed to overcome the current limitations in the field and solve the stated questions. Our working hypothesis is that RANK may be a superior therapeutic target than RANKL and that RANK signaling governs epithelial stem cell homeostasis and lineage commitment and regulates cancer progression and metastasis in epithelial tumors through: i) intrinsic effects in CSCs and bulk tumor cells and ii) extrinsic effects, driven by tumor-immune cells crosstalk and tumor immunity.

ERC Consolidator Grant (ERC-CoG)

Título/Title: TOPOmics: Project Global dynamics of topoisomerase-induced DNA breaks
Ref.: 647359
Investigador Principal/Principal Investigator: Cortés Ledesma, Felipe
Fecha Inicio/Starting Date: 01/06/2019
Fecha Fin/Ending Date: 31/12/2025
Presupuesto/Budget: 2.000.000,00 €
Comentarios/Comments: HORIZON 2020 (2014-2020). Transferred to CNIO.

Resumen/Summary

This project aims at acquiring a comprehensive picture of the dynamics of topoisomerase-induced DNA breaks: from their occurrence and repair to the consequences for genome expression and integrity. We rely on the development of completely novel assays to detect and isolate the different intermediates of topoisomerase-induced break repair, and which overcome major traditional limitations in the field. These tools are subsequently used to integrate the time-dependent and genome-wide distribution of the different steps and final outcomes of the process of topoisomerase-induced DNA break repair. Furthermore, we outline original proteomic and genetic screenings to identify novel factors and pathways specifically involved the cellular response to this important type of DNA lesion.

ERC Consolidator Grant (ERC-CoG)

Título/Title: ALTER-brain: Metastasis-associated altered molecular patterns in the brain
Ref.: 864759
Investigador Principal/Principal Investigator: Valiente Cortés, Manuel
Fecha Inicio/Starting Date: 01/07/2020
Fecha Fin/Ending Date: 30/06/2025
Presupuesto/Budget: 1.897.473,00 €
Comentarios/Comments: HORIZON 2020 (2014-2020)

Resumen/Summary

Organ colonization is the most inefficient step of metastasis. However, once a few cancer cells manage to re-initiate their growth in the brain, the initial naïve microenvironment, which was not favouring and even actively limiting the number of potential metastasis initiating cells, is slowly rewired into a different ecosystem with pro-metastatic properties. In this project (ALTER-brain), we will study the biology of microenvironment reprogramming to explore innovative ways of treating metastasis.

Microenvironment reprogramming relies on altered molecular patterns that emerge in specific brain cell types simultaneously to the outgrowth of metastases. Dissecting the biology of these emerging patterns and their functional consequences could provide the basis to prevent metastasis but also to treat advances lesions. A key objective of ALTER-brain is the identification of newly established functional networks among previously non-connected components of the microenvironment that are critical to nurture tumour growth.

This research proposal focuses on metastasis in the brain given its rising incidence, poor therapeutic options and short survival rates upon diagnosis. ALTER-brain will use novel (i.e. spontaneous metastasis) and clinically relevant (i.e. relapse after therapy) experimental mouse models of brain metastasis combined with genetically engineered mice in which we will target specific components of the microenvironment. In addition, we will apply novel lineage tracing technologies to understand the origin and emerging heterogeneity of the reprogrammed microenvironment. Given the clinical relevance of our research, human brain metastasis provided by our clinical network will be used to validate key findings.

ALTER-brain will identify key principles underlying the unknown biology of the brain under a specific pathological pressure that might be translated to other highly prevalent disorders affecting this organ in the future.

ERC Starting Grant (ERC-Stg)

Título/Title: NutrientSensingVivo: The Physiology of Nutrient Sensing by mTOR
Ref.: 638891
Investigador Principal/Principal Investigator: Efeyan, Alejo
Fecha Inicio/Starting Date: 01/01/2016
Fecha Fin/Ending Date: 31/12/2020
Presupuesto/Budget: 1.846.494,00 €
Comentarios/Comments: HORIZON 2020 (2014-2020)

Resumen/Summary

A major role of metabolic alterations in the development of several human diseases, as diabetes, cancer and in the onset of ageing is becoming increasingly evident. This has a deep impact for human health due to the alarming increase in nutrient intake and obesity in the last decades. Fundamental aspects of how aberrant nutrient fluctuations trigger deregulated hormone levels and endocrine signals have been elucidated, being a prime example the phenomenon of insulin resistance. In contrast, how changes in nutrient levels elicit direct cell-autonomous signal transduction cascades and the consequences of these responses in physiology are less clear.

The signalling circuitry of direct nutrient sensing converges with that of hormones in the regulation of the mechanistic target of rapamycin (mTOR) kinase, a driver of anabolism, cell growth and proliferation. Deregulation of mTORC1 activity underlies the pathogenesis of cancer and diabetes, and its inhibitor rapamycin is approved as an anti-cancer agent and delays ageing from yeast to mammals. In spite of its importance for human disease, our understanding of the nutrient sensing signalling pathway and its impact in physiology is largely incomplete, as only a few years ago the direct molecular link between nutrients and mTORC1 activation, the Rag GTPases, were identified.

The present proposal aims to determine how the nutrient sensing signalling pathway affects mammalian physiology and metabolism, and whether its deregulation contributes to cancer, insulin resistance and aging. In particular, the objectives are: 1) To identify novel regulators of the Rag GTPases with unbiased and candidate-based approaches. 2) To establish the consequences of deregulated nutrient-dependent activation of mTORC1 in physiology, by means of genetically engineered mice. 3) To determine the impact of the nutrient sensing pathway in the effects of dietary restriction and nutrient limitation in glucose homeostasis and cancer.

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