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CNIO Friends newsletter 39

06.08.2021

Research needs you

COLUMN

Dear Friends,

In the past few months, we made some new discoveries that we hope will help us move forward in the diagnosis and treatment of cancer and other diseases. You can read about them in the Science News section in this newsletter. In addition, we carried out two important activities framed within CNIO Friends, our initiative to support research at the CNIO by hiring new researchers.

On June 23, we held our CNIO Friends Day (link to the event; in Spanish), an event to thank our Friends for their support. This year, our guest was Edurne Pasaban, the first woman to climb all 14 eight-thousanders, who has always shown her support. Furthemore, the researchers hired through the CNIO Friends initiative shared the latest developments in their research projects.

In July, we held the 4th CNIO Arte event, coinciding with Spain’s International Contemporary Art Fair ARCO (link to the presentation). It was a special edition indeed, as ARCO generously gave us the chance to have our own stand at the fair and to show all the works produced in the context of CNIO Arte so far. This included this year’s project, by visual artist Daniel Canogar, inspired by big data in everyday life and his talks with Sarah Teichmann, from the UK-based Wellcome Sanger Institute. Canogar’s work, Fulguraciones, was on display at the entrance hall of the CNIO from June 11 to early July, for all the CNIO researchers to contemplate. Then it was transferred to ARCO; after the fair, it came back to CNIO, where it will be shown until September.

As part of CNIO Arte, we held the 2nd CNIO Art and Science Symposium (link to the event; in Spanish), under the title “Mapping in the Digital Age”. It was a forum to discuss how the big amounts of data circulating in the digital society are reshaping human identity.

CNIO Arte would not be possible without the support of Fundación Banco Santander and the British Embassy. I would like to thank them for this.

In these past months, we made eight new cancer research contracts available with the help of our donors. Thanks to you, our more than 2000 Friends, the CNIO has raised 2.4 million euro since the CNIO Friends community was established six years ago. All donations go to the CNIO Post-Doctoral Research Contract Programme, that is aimed at retaining research talent and opening new lines of cancer research in fields such as metastasis, childhood cancer, and liver and kidney cancer.

Last but not least, I would like to mention our pioneering partnership with Fondation Franz Weber – now a CNIO Friend –, thanks to which we will be able to boost the development of research projects using alternatives to animal testing. This partnership shows CNIO’s commitment to good practices in animal experimentation, including the development of alternative methods.

We are very proud of the CNIO’s institutional achievements. I hope you enjoy reading our latest news. Once again, thank you very much for your support! I wish you a great summer.

Maria A. Blasco
Director

Meet the CNIO Friends researchers

Sergio Muñoz

Sergio Muñoz. /A.Tabernero. CNIO  Sergio Muñoz. /A.Tabernero. CNIO

“I would like to thank CNIO Friends for their generous donations that support this initiative, which has enabled me to conduct my research in DNA replication and genomic instability.” Today we would like to highlight the work being done by Sergio Muñoz, who joined the lab managed by Juan Méndez as part of the DNA Replication Group to carry out a project aimed at understanding how errors in DNA replication lead to genomic instability, a process that is associated with several types of cancer.

Sergio completed his PhD at the CNIO and then did his postdoctoral training at the University of Seville. He has now returned to the CNIO to study the mechanisms underlying genomic instability, mainly because there are many groups working in this field at the Centre, which makes it an appropriate environment for collaboration and joint research in the area.

As a university undergraduate studying basic science, Sergio realised that many fundamental cellular processes can lead to cancer development when they go wrong. As a result, he chose cancer research as his field of study: “We all know somebody who has had cancer, so this is a good way of making a contribution to society.”

“The project I am working on right now includes a system to study errors in duplication in cancer cells. We are focusing on 60 genes associated with replication, removing them one by one to see if their removal prevents or exacerbates duplication. At the same time, we are studying how to create physical barriers in DNA to limit this phenomenon. It is an exciting project, and I am so glad to be back at the CNIO!”

We are very happy to have Sergio Muñoz back at the CNIO too. Thank you, CNIO Friends, for supporting Sergio in his research!

CNIO Science News

Mouse motor neurons, generated from mouse embryonic stem cells exposed (right) or not (left) to ALS-associated peptides (right). As observed in patients, these peptides are toxic and cause neuronal death. /CNIOMouse motor neurons, generated from mouse embryonic stem cells exposed (right) or not (left) to ALS-associated peptides (right). As observed in patients, these peptides are toxic and cause neuronal death. /CNIO

The team led by Óscar Fernández-Capetillo has found the cause of neuronal death in a great number of familial ALS patients. Symptoms of ALS, whose causes are still unknown, include muscle weakness and stiffness. According to the researchers, a new mechanism, which blocks the cellular reactions involving nucleic acids (DNA or RNA), could be responsible for the destruction of nerve cells.

More information

Senescent epithelial cells (cyan) in a mouse mammary gland with high levels of RANK protein. RANK-induced senescence is essential for stem cell accumulation and, despite it initially delays tumor growth, it ultimately promotes tumor progression and metastasis. /CNIOSenescent epithelial cells (cyan) in a mouse mammary gland with high levels of RANK protein. RANK-induced senescence is essential for stem cell accumulation and, despite it initially delays tumor growth, it ultimately promotes tumor progression and metastasis. /CNIO

Eva González-Suárez and her team have found that hyperactivation of the RANK pathway plays a double function in breast cells. In the early stages of cancer, it activates senescence, which has a protective effect and delays the appearance of tumours. In more advanced stages, RANK-induced senescence favours the accumulation of stem cells in the breast tissue, which promotes tumour growth. RANK inhibitors are currently being developed as a means to prevent cancer aggressiveness.

More information

Artist’s rendering of the subcomplex that constitutes the T7SS secretion system of Artist’s rendering of the subcomplex that constitutes the T7SS secretion system of 'M. tuberculosis' embedded in the cell membrane. /CNIO

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which affects primarily the lungs. It is the deadliest infectious disease in history and still is among the world’s ten leading causes of mortality. The teams led by Óscar Llorca at the CNIO and Sebastian Geibel at the University of Würzburg, Germany, published a review article on the latest findings on the system used by bacteria to transport and export virulence factors. The goal is to understand this system and develop molecules that can block it in order to stop the infection.

More information

The director of the study, Juan Méndez, in the center, together with the researchers Elena Blanco-Romero, on the left, and Patricia Ubieto-Capella, on the right. /A.Tabernero. CNIOThe director of the study, Juan Méndez, in the center, together with the researchers Elena Blanco-Romero, on the left, and Patricia Ubieto-Capella, on the right. /A.Tabernero. CNIO

The team led by Juan Méndez found that PrimPol, a protein involved in DNA reparation, could be used to enhance the therapeutic effects of chemotherapy. The team are now trying to block PrimPol in order to make tumour cells more sensitive to cancer treatments and enhance the effectiveness of chemotherapy.

More information

From left to right: Ana Belén-Plata Gómez, Alejo Efeyan, and Nerea Deleyto-Seldas. /A.Tabernero. CNIOFrom left to right: Ana Belén-Plata Gómez, Alejo Efeyan, and Nerea Deleyto-Seldas. /A.Tabernero. CNIO

The human body has adapted to feeding-fasting cycles throughout the evolution of organisms. The group of researchers headed by Alejo Efeyan found that activation of the RagA protein is key in this process. They are now studying the possibility of blocking signals to simulate the fasting effects without the disadvantages of limited food intake.

More information

Structure of the proteins determined in the article, together with the rest of the proteins that form the complex that manages the assembly of mTOR /CNIOStructure of the proteins determined in the article, together with the rest of the proteins that form the complex that manages the assembly of mTOR /CNIO

It is estimated that at least 60% of tumours show some form of modification in mTOR or proteins that interact with it. The team headed by Óscar Llorca identified the shape of proteins that interact with mTOR in atomic detail, which will help understand how these nanomachines work and design new cancer treatments.

More information

Alejo Efeyan, Head of the CNIO Metabolism and Cell Signalling Group, and Ana Ortega-Molina, first author of the study. / A.Tabernero. CNIOAlejo Efeyan, Head of the CNIO Metabolism and Cell Signalling Group, and Ana Ortega-Molina, first author of the study. / A.Tabernero. CNIO

The team coordinated by Alejo Efeyan showed that blocking the signals regulated by RagC in animal models can delay the onset of follicular lymphoma with no side effects. The strategy might be also effective in treatments for autoimmune diseases. The researchers are now looking for inhibitors of these signals to be used in humans.

More information

Lung carcinoma induced by KRAS4A. / CNIOLung carcinoma induced by KRAS4A. / CNIO

It has been well known for almost four decades that KRAS oncogenes are responsible for 25 per cent of all human tumours, including some of the most malignant cancers, such as lung or pancreatic cancer. Unfortunately, there are no really effective drugs for these tumours, except for Sotorasib, which has been approved recently. A study by the Experimental Oncology Group, headed by Mariano Barbacid, shows that the two proteins produced by KRAS can cause cancer, which means that only treatments targeted at both isoforms will be effective.

More information

Our Centre

In addition to the Annual CNIO Friends Day, the CNIO Arte event and the eight new research contracts made available with the support of our donors, we would like to point out other relevant developments at the Centre.

Our researchers Alejo Efeyan and Héctor Peinado are the recipients of two Leonardo Grants, worth 40,000 euro each. In addition, the CNIO participated in the 15th Diverciencia International Conference in Algeciras. Due to the pandemic, the event was held online, offering the 32,000 visitors – 10,000 more than the previous year – 90 stands, one of which belonged to the CNIO.

Finally, on July 13, Marisol Soengas, Head of the Melanoma Group and Dean for Academic Affairs at the CNIO, was appointed as a Corresponding Member of the Spanish Royal Academy of Pharmacy (RANF). The appointment ceremony, held via zoom, was hosted by Antonio Ramón Martínez Fernández, Secretary and Full Member of RANF. Two other CNIO researchers are RANF members, namely, Mariano Barbacid and Maria A. Blasco. They were appointed in 2011 and 2013, respectively.

INTERVIEW

Eva González Suárez / A.Garrido. CNIOEva González Suárez / A.Garrido. CNIO

Eva González Suárez is the Head of the Transformation and Metastasis Group at the CNIO.

What are your goals for the study of metastasis?

In our laboratory, we explore new treatments for the survival of patients with epithelial cancer, mainly breast cancer, associated with metastasis. Metastasis is the primary cause of mortality in these patients, as the primary tumour can be easily removed through surgical resection. We need to understand metastasis and the physiology of normal tissue better, as cancer cells do not do anything new but use the same mechanisms as normal cells, only anomalously.

One of your goals is to study whether RANKL inhibitors might be effective in preventing breast cancer. How do you know this might be so?

Our results regarding prevention are very clear in all animal models, as well as in human breast cells. Inhibiting the RANKL pathway using a drug that is being used in osteoporosis with few side effects is highly effective in the prevention of breast cancer. Of course, this preventive treatment is recommended for patients with an increased risk of breast cancer, such as women with a family history of cancer (inherited mutations BRCA1 or BRCA2). Taking this drug for osteoporosis twice a year might prevent mastectomy, which is the only way to reduce the risk of developing breast cancer at present.

What are the implications for breast cancer patients?

Once cancer is detected, treatment scenarios are far from simple. Breast cancer is a very complex, heterogeneous disease. It depends on the expression of hormone receptors, proteins like HER2, and on when cancer sets in, before or after menopause. Our results in mice models so far show that inhibiting the RANKL pathway might reduce cell division rates and lead to cell death in some types of breast cancer. Besides, clinical and preclinical trials show that inhibiting this pathway reactivates the anticancer immune response, thus enhancing immunotherapy effectiveness.

We are conducting preclinical trials with tumours from breast cancer patients and clinical trials as well. Our goal is to identify biomarkers for the selection of women with breast cancer who could benefit from the drug.

You were awarded an ERC Consolidator Grant. Do you believe there should be more grants like this one?

Absolutely. Funding of basic research is inadequate, not only in Spain (spending on basic research accounts for 1.25% of GDP) but also in Europe (around 2% of GDP on average). Most research funding in Europe goes to consortiums and applied or translational research. Even though applied research builds on basic research, the funds granted to the latter are not enough.

During the current pandemic, everybody could see that vaccines were developed in less than a year. It is clearer than ever that investing in basic research pays off, since the discovery of DNA, RNA, RNA viruses or immune response was made possible by basic research.

The ERC programme is an honourable exception – an excellent opportunity to get funding for basic research. Despite the remarkable success of Spanish researchers in ERC calls, they make only a small minority of the total number of researchers working in Spain. ERC Starting and Consolidator grants are awarded to individual researchers in the early stages of their careers or to scientists who want to strengthen their position and then pursue their career through high-level funding in their countries. The problem is that in Spain such high-level funding does not exist. Public funding projects in this country give ten times less money than the ERC programme.

Breast cancer is among the types of cancer with the sharpest fall in death rates in the last decades. What are the expectations for the coming years?

That is right, much has been achieved thanks to (relatively) heavier investment in breast cancer research than in other types of cancer. This clearly indicates that more funds lead to more successful projects and ultimately to increased survival. I think that in the coming years, we will deepen our knowledge of the heterogeneity of the disease and survival rates will continue to increase as a result of new targeted therapies and a more precise selection of eligible patients. I think we will be able to improve patients’ response to immunotherapy (with findings like ours, enabling us to recommend Denosumab to enhance the response to immunotherapy) and also preventive treatments.

When will the new therapies you are studying be available to breast cancer patients?

Some of them are now available. The problem is, if the patients or the treatment protocols or the combination of drugs are not adequately selected, some of the therapies that could be highly beneficial may end up being discarded.

There should be a more rational approach to clinical trials and combination therapies, and we should increase the number of window of opportunity studies that enable us to identify biomarkers to predict response to treatments.

PROFILE

Sarah Teichmann

Sarah Teichmann / A.Garrido. CNIOSarah Teichmann / A.Garrido. CNIO

When she was appointed as a member of the UK Academy of Medical Sciences in 2015, Sarah Teichmann was described by her colleagues as “the representative of a new lineage of scientists at the interface between computational biology and experimental molecular biology.”

Teichmann (Karlsruhe, Germany, 1975) is a computational biologist. She leads the Human Cell Atlas project, which gathers almost 300 labs from all over the world to map the dozens of trillions of cells of hundreds of different types that make the human body.

Teichmann’s research focuses on the global principles that govern protein-protein interactions and their gene expression. She is Head of Cellular Genetics at the Wellcome Trust Sanger Institute in Cambridge, UK, and Senior Group Leader at EMBL-European Bioinformatics Institute. She works alongside biologists, developers, physicists and mathematicians.

Sarah did her PhD at the MRC Laboratory of Molecular Biology, Cambridge, UK, and was a Beit Memorial Fellow at University College London. She started a group at the MRC Laboratory of Molecular Biology in 2001. In 2013, she moved to the Wellcome Genome Campus in Hinxton, Cambridge, where her group was joint between the EMBL-European Bioinformatics Institute and the Wellcome Sanger Institute.

Teichmann is a member of the European Molecular Biology Organization (EMBO) and fellow of the Academy of Medical Sciences, and her work has been recognised by a number of , including the Lister Prize, the Biochemical Society Colworth Medal, the Royal Society Crick Lecture and the EMBO Gold Medal in 2015.

Distinguished Seminars

07.05.2021
Agata Smogorzewska
The Rockefeller University (United States)
'Tumorigenesis in the setting of DNA interstrand crosslink repair deficiency'


21.05.2021
Sara Buhrlage
Dana-Farber Cancer Institute (United States)
'Integrated platform for DUB inhibitor discovery'


04.06.2021
Pascale Cossart
Pasteur Institute (France)
'Infection biology in the era of microbiomes: the Listeria paradigm'


11.06.2021
Asifa Akhtar
Max Planck Institute of Immunobiology and Epigenetics (Germany)
'X chromosome: A paradigm to study epigenetic regulation'


18.06.2021
Nuria Sebastián
Pompeu Fabra University
'Languages before language: Infants’ early steps to learn language(s)'


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