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Maria Blasco and Marisol Soengas. / ©Amparo Garrido. CNIO
From 185 grants awarded by the European Research Council (ERC), 14 have gone to Spain; four of them in the field of life sciences, including the two received by the CNIO researchers
The SHELTERINS and METALERT-STOP projects will face two of the major pending challenges of oncology: the immortality of cancer cells and their ability to lead to metastasis
Maria Blasco will do the first systematic study of shelterin proteins, known to be mutated in various types of cancer, to try to abolish the capacity of tumour cells to divide indefinitely
Marisol Soengas will use sophisticated techniques and animal models to understand how metastases arise and how to treat them more efficiently; the results obtained will be validated in patient samples
These two grants, together with Mariano Barbacid’s 'ERC Advanced Grant', three 'ERC Consolidator Grants' of Manuel Valiente, Felipe Cortés and Eva González, and an 'ERC Starting Grant' of Alejo Efeyan bring the CNIO grants from the European Research Council to a total of seven
Two of the major pending questions in the field of oncology are why tumour cells can divide indefinitely, and how they are able to spread throughout the body. Maria Blasco, Head of the Telomeres and Telomerase Group of the Spanish National Cancer Research Centre (CNIO) and Scientific Director of the CNIO, and Marisol Soengas, Head of the Centre’s Melanoma Group, just received two of the most competitive grants from the European Research Council (ERC), the ERC Advanced Grants, to carry out two ambitious projects that will try to block the unrestrained division of cancer cells and their spread to other organs, respectively.
They each receive 2.5 million euros, the maximum amount stipulated for these grants, to carry out their SHELTERINS and METALERT-STOP projects over the next 5 years. Their projects have been selected in a highly competitive process from among almost 1,900 proposals by top-level European researchers. From 185 grants awarded by the ERC, 14 have gone to Spain; four of them in the field of life sciences, including the two received by the CNIO researchers.
ERC Advanced Grants are awarded to projects that have the ability to open very innovative and original research lines and contribute to solving scientific challenges that remain to be elucidated; they must be carried out by European researchers who are leaders in their respective fields and have a track record of novel, original and important research achievements in the last 10 years.
The grants now obtained by the two Spanish researchers are added to five other grants currently held by the CNIO: an ERC Advanced Grant of Mariano Barbacid, three ERC Consolidator Grants of Manuel Valiente, Felipe Cortés and Eva González, and an ERC Starting Grant of Alejo Efeyan.
Abolishing the capacity of tumour cells to divide indefinitely
The SHELTERINS project, led by Maria Blasco, will focus on better understanding the role of shelterin proteins in cancer, to find therapeutic strategies that put an end to the ability of tumour cells to divide indefinitely by disrupting telomere protection and thus block the potential unrestrained growth of tumours.
Shelterins are proteins that make up the protective shield for telomeres. Telomeres are essential for the life of a cell. In healthy cells, they shorten over time and this is one of the causes of tissue ageing and the appearance of age-related diseases. By contrast, cancer cells are able to keep their telomeres long and thus become immortal cells that are able to divide in an uncontrolled fashion. For that reason, therapeutically attacking telomeres is one of the most promising strategies against many types of cancer.
“Shelterins are the proteins that protect the telomeres, without them cancer cells cannot multiply,” explains Blasco. “My team was a pioneer in proposing shelterins as possible targets against cancer. We also contributed to discovering the first shelterin mutations in cancer and we demonstrated that their function is regulated by important cancer signalling pathways.” In recent years, Blasco’s team also showed that elimination of the shelterin protein TRF1 blocks the initiation and progression of lung cancer and glioblastoma in mouse tumour models. Her group also discovered that eliminating TRF1 prevents glioblastoma stem cells from forming secondary tumours.
However, the investigation of this promising pathway is in its infancy: the mechanisms that cause shelterins to induce tumour development are still unknown and there are no animal models to work on these ideas. The SHELTERINS project will make the first major worldwide systematic approach in this field of study.
On the one hand, it will generate mouse models to try to understand the role of shelterin mutations in cancer, specifically in the shelterin POT1; this protein is mutated in many types of tumours including gliomas (tumours of the nervous system for which there are currently few treatments). The aim is to find new strategies against these tumours.
On the other hand, Blasco also wants to establish the role of TRF1 in tumour stem cells, malignant cells that are central to cancer development and that can generate new tumours. “In 2017, we saw how blocking this shelterin in glioblastoma stem cells in mice increased their survival. Exploring these results further will allow us to learn more about the functions of this protein so that we can find therapeutic strategies that make use of it.”
This is the second time that Blasco obtained one of these important grants. The ERC evaluation committee highly valued the achievements of Blasco and her team throughout her research career. They also very much appreciated the innovative nature of the project, as it is the first time that a systematic study of shelterins has been proposed to answer preclinical questions that are expected to be of significant help for the advance of cancer treatment.
How to turn off mice that light up when they metastasise
One of the great challenges in melanoma research is to understand how some lesions just over 1 mm thick can give rise to cells that can spread throughout the body and cause more than 80% of skin cancer-related deaths. Soengas’s group has described multiple genes that define the melanoma fingerprint that makes it so metastatic, and it is focused on intervening in earlier stages of the disease and to eliminate metastases once they are generated. The METALERT-STOP project, led by Marisol Soengas, will concentrate on understanding how metastases arise so they can be treated more efficiently. To do this, they will use very sophisticated animal models and validate the results in patient samples.
The Soengas team already managed in 2017 to visualize for the first time in living organisms and without resorting to surgery or invasive interventions, how melanoma spreads throughout the body even before metastases appear. This monitoring of melanoma was achieved thanks to bioluminescent mouse models called MetAlert, developed in collaboration with the Mouse Genome Editing Core Unit led by Sagrario Ortega at the Centre. MetAlert lights up where the generation of lymphatic vessels is activated; lymphatic vessels are a type of vessel in the circulatory system whose generation is one of the essential steps for the spread of this type of tumour. The importance of this work, which was carried out together with many national and international basic and clinical research groups, earned it a publication in Nature, one of the world’s leading scientific journals.
Furthermore, the study identified a protein called MIDKINE as a possible therapeutic target. “In subsequent studies, we have seen that MIDKINE is not only involved in the generation of lymphatic vessels but also has other unexpected functions,” explains Soengas. “For example, we found that MIDKINE helps prevent the immune system from recognising and attacking tumours. We were also surprised to see that it seems to regulate many pathogen sensors, which could, in turn, have an effect on tumour development.”
MetAlert, MIDKINE and their immunomodulatory effects were highlighted by the evaluation committee of the ERC for their great importance, since many answers regarding the diagnosis, monitoring and treatment of melanoma still need to be resolved.
METALERT-STOP will use the MetAlert mice and other models the group has designed to determine where and when the early stages of the dissemination process can be visualised in vivo. It will also study the mechanisms involved in this activation of metastasis, including various environmental risk factors. Finally, the researchers have a third objective aimed at finding therapies: “We have these mice that light up when there are processes of metastasis. The question now is: how do we turn them off?,” summarises Soengas. “The results of the study will be validated in samples from patients who are in different stages of treatment.”
Furthermore, Soengas believes that the results of the project will be very useful for understanding the processes of metastasis in other tumour types, such as gliomas and glioblastomas, and liver or lung carcinomas. “This potential has also been very important for awarding the grant,” she concludes.
About Maria Blasco
Maria Blasco, Head of the CNIO Telomeres and Telomerase Group and Director of the CNIO, is a molecular biologist dedicated to studying the role of telomeres and telomerase in cancer and ageing; she is a world leader in this field of research. She has contributed to the identification of mammalian telomerase genes and generated the first telomerase-deficient mice. These mice were instrumental in demonstrating that short telomeres are sufficient to induce ageing. Together with her group, she has shown that it is possible to delay ageing and its associated diseases by activating this enzyme. Her studies have been published in the most important scientific journals such as Cell, Nature, Science and Cell Stem Cell.
Her achievements have been recognised through prestigious international awards such as the Josef Steiner Cancer Research Award from Switzerland, the Körber European Science Award from Germany, the Gold Medal from the European Molecular Biology Organization (EMBO), as well as the National Santiago Ramón y Cajal Award in Biology and the Rey Jaime I Award. Blasco is vice-chair of the Severo Ochoa Centres of Excellence and the María de Maeztu Units of Excellence Alliance (SOMMa) and she has also received three honorary doctorates in Spain from the Carlos III University of Madrid (2014), the University of Alicante (2017), and the University of Murcia (2018). She served as Editor or Monitoring Editor of different scientific journals such as Cancer Research and Journal of Cell Biology, as well as serves in different Scientific Advisory Boards in Spain and abroad. In 2020, Blasco was appointed member of the Board of Trustees of the Prado Museum, Madrid.
About Marisol Soengas
Marisol Soengas, Head of the CNIO Melanoma Group, is an international expert in basic and applied melanoma research. The main objective of her group is to understand the initiation and progression of this tumour, and how to attack it more efficiently. Her studies have been published in the highest impact scientific journals such as Nature, Cell, Cancer Cell and Science.
She has received numerous awards, the most recent of which include the Atresmedia ‘Constants and Vitals’ Award for the Most Important Biomedical Publication of 2017, and the 2017 ‘Women Executives of Galicia’ Award for her scientific career. In 2018, she received the ‘Plaque of Honour’ from the Spanish Association of Scientists. In 2019, she received the Fritz Anders Medal from the European Society for Pigment Cell Research (ESPCR), the Sesderma Award for Influential Women in Science and Innovation, and the 2019 Science and Woman Commendation from WomenCEO. She is an elected member of the management board of the Confederation of Spanish Scientific Societies (COSCE), as well as of the Spanish Association for Cancer Research (ASEICA), where she has founded and coordinates the ASEICA-Women working group.