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CNIO Friends Newsletter 35

05.11.2020

Help us to stop cancer

Column

Dear Friends,

One of the lessons we have learned from the Sars-Cov-2 pandemic is that humankind is vulnerable and it is science that gives us hope for solutions to this health crisis and other global crises that may occur in the future. In less than a year, scientists from all over the world acted in a coordinated, systematic and cross-border manner, to find the virus that caused the disease and to understand its mechanism of infection in order to generate vaccines and find effective treatments against this new disease.

Similarly, the only way to offer the hope that more cancer patients will be cured every day is through research. On September 24, we celebrated World Cancer Research Day at the CNIO with a conference entitled A new era in cancer research: towards the engagement of the entire society. Apart from highlighting the importance of basic research as a driving force for new advances by means of the seminar given by Spanish scientist Francis Mojica, who discovered the CRISPR system, we also underlined the necessary participation of citizens in an area that directly affects them through initiatives such as ‘CNIO Friends’. I encourage you to see the whole of this interesting event following this link.

Our special guest at this meeting, Francis Mojica, is an example of genuine vocation and enthusiasm. His basic discovery a few decades ago in the DNA of certain bacteria is the bedrock of the CRISPR gene-editing technique, which recently won the Nobel Prize for Chemistry for its potential to revolutionise research into diseases such as cancer. It is the best example of the fact that science is a long-distance race, that we cannot ignore any of its steps, however anecdotal they may seem – as their implications can be immense, and that any obstacle, however small, means delays that we cannot afford in order to continue improving our health and quality of life.

Maria A. Blasco
Directora

CNIO Science News

Illustration and Computed Tomography image of the therapeutic effect before and after CDK4 and RAF1 inactivation. On the left two tumors can be observed when KRAS is activating the downstream CDK4 and RAF1. On the right, the same tumours disappearing upon CDK4 and RAF1 inactivation. <b>/CNIO</b>Illustration and Computed Tomography image of the therapeutic effect before and after CDK4 and RAF1 inactivation. On the left two tumors can be observed when KRAS is activating the downstream CDK4 and RAF1. On the right, the same tumours disappearing upon CDK4 and RAF1 inactivation. /CNIO

A team from the Experimental Oncology Group led by Mariano Barbacid achieved regression of lung tumours caused by KRAS in mice.

The KRAS oncogene is involved in at least one-fifth of all human cancers, but effective therapeutic strategies against this oncogene have not yet been developed. Now, the CNIO has achieved complete remission in 25% of tumours by inactivating CDK4 and RAF1 (two genes that act at different levels in the signalling pathway of this oncogene). Moreover, this therapeutic combination slowed tumour growth in 100% of the cases.

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Immunohistochemical analysis of E-cadherin (ECad) and R-cadherin (RCad) in normal skin samples from breast cancer patients before starting capecitabine treatment. Unlike ECad (top), RCad (bottom) expression is mostly observed in the suprabasal epidermal layers, which are affected in the hand-foot syndrome. <b>/CNIO</b>Immunohistochemical analysis of E-cadherin (ECad) and R-cadherin (RCad) in normal skin samples from breast cancer patients before starting capecitabine treatment. Unlike ECad (top), RCad (bottom) expression is mostly observed in the suprabasal epidermal layers, which are affected in the hand-foot syndrome. /CNIO

Administering the chemotherapy drug capecitabine in breast and colorectal cancer increases the life expectancy of patients with these cancers. However, some patients experience an adverse skin reaction called hand-foot syndrome, which, when severe, makes dose reductions or even discontinuation of treatment necessary.

Now, a team led by Anna González-Neira, Head of the Human Genotyping-CEGEN Unit, has identified the genetic variants of patients genetically predisposed to suffering this adverse reaction to capecitabine. This finding is crucial in order to identify, before starting treatment, people who may develop this toxic reaction and, therefore, be able to personalise the therapy.

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Representative images of an untreated tumor (left) compared to another tumor (right) treated with the CRISPR gene editing system for elimination of fusion genes. Cells are stained with a cell proliferation marker (Ki67). Brown staining indicates a high rate of cell proliferation in the untreated tumor, while the absence of staining (cells in blue) indicates that the CRISPR-treated tumour has stopped its growth. <b>/CNIO</b>Representative images of an untreated tumor (left) compared to another tumor (right) treated with the CRISPR gene editing system for elimination of fusion genes. Cells are stained with a cell proliferation marker (Ki67). Brown staining indicates a high rate of cell proliferation in the untreated tumor, while the absence of staining (cells in blue) indicates that the CRISPR-treated tumour has stopped its growth. /CNIO

Researchers led by Sandra Rodríguez-Perales, Head of the Molecular Cytogenetics Unit, have managed for the first time to destroy Ewing’s sarcoma and chronic myeloid leukaemia cancer cells without affecting healthy cells, using CRISPR gene-editing techniques to eliminate the fusion genes that cause these tumours.

Fusion genes (the result of an abnormal joining of DNA from two different genes) are unique to tumour cells, which is why they are excellent targets for the development of future drugs that only attack the tumour and do not harm healthy cells. The team will study whether the strategy is also effective in other types of cancer for which there are currently no effective therapies.

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Marisol Soengas, Head of the CNIO’s Melanoma Group (centre), with David Olmeda, co-author of the study, and Daniela Cerezo, first author. <b>/A. Garrido, CNIO</b>Marisol Soengas, Head of the CNIO’s Melanoma Group (centre), with David Olmeda, co-author of the study, and Daniela Cerezo, first author. /A. Garrido, CNIO

The Melanoma Group headed by researcher Marisol Soengas at the CNIO has managed to understand how melanoma succeeds in deceiving the immune system, not only by preventing it from attacking the tumour but even to turn it into an ally that helps the tumour grow.

A key element in this deception is MIDKINE, a protein that modifies the function of several components of the immune system. The good news is that, by blocking MIDKINE, the team managed to get the immune cells to attack the tumour again. This finding will help improve immunotherapy, a strategy with great potential for treating cancer but which is not yet fully effective.

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Islet of Langerhans with beta cell-secreting insulin (in red) and alpha cell-secreting glucagon (in green). <b>/CNIO</b>Islet of Langerhans with beta cell-secreting insulin (in red) and alpha cell-secreting glucagon (in green). /CNIO

Researchers of the Growth Factors, Nutrients and Cancer Group led by Nabil Djouder described for the first time how a virus can cause diabetes by affecting the functions and identity of insulin-generating cells in the pancreas. This phenomenon was already known, but its molecular mechanism was not understood.

The team suggests exploring whether the potential of some compounds already tested for cancer treatment in combination with antiviral therapies could be effective as a prevention and therapeutic strategy. Moreover, the finding might be relevant to address the COVID-19 pandemic, as recent clinical information indicates that the virus that causes this disease also causes diabetes in some patients.

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Our Centre

From left to right, top to bottom: Francis Mojica, Sandra Rodríguez-Perales, Sonia Vidal, María Luisa Villafranca, Maria Blasco, Cristina Villanueva, and Luis Paz-Ares. <b>/CNIO</b>From left to right, top to bottom: Francis Mojica, Sandra Rodríguez-Perales, Sonia Vidal, María Luisa Villafranca, Maria Blasco, Cristina Villanueva, and Luis Paz-Ares. /CNIO

On September 24, on the occasion of World Cancer Research Day, we organised the event A new era in cancer research: towards the engagement of the entire society.

Francis Mojica, tenured Professor of the Department of Physiology, Genetics and Microbiology at the University of Alicante, gave the keynote address ‘Solving riddles, fighting disease, delighting in CRISPR’.

This was followed by a panel discussion moderated by Cristina Villanueva to debate the challenges of the future and society’s involvement in tackling them, with the participation of Maria A. Blasco, Director of the CNIO and Head of the Centre’s Telomeres and Telomerase Group; Luis Paz-Ares, Head of the H12O-CNIO Lung Cancer Clinical Research Unit and Head of the Medical Oncology Service at the 12 de Octubre University Hospital; Sandra Rodríguez-Perales, Head of the Molecular Cytogenetics Unit at the CNIO; and María Luisa Villafranca, breast cancer patient and President of the Rosae Association, a member of CNIO Friends.

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Recruitment of immunosuppressive cells (pink) in aggressive melanoma tumours with high levels of Midkine (green). <b>/CNIO</b>Recruitment of immunosuppressive cells (pink) in aggressive melanoma tumours with high levels of Midkine (green). /CNIO

The Melanoma Group headed by Marisol Soengas at the CNIO received funding under the Health Research Call of the “la Caixa” Foundation, to describe the immune mechanisms that favour tumour progression and propose therapeutic strategies to block them.

In this same call, the Foundation also selected an IRB project involving Óscar Llorca, Head of CNIO’s Macromolecular Complexes in DNA Damage Response Group, to use cryo-electron microscopy to further our understanding of brain physiology.

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Image of the first Spikebody prototype. Synthetic immunology will be used as a tool to engineer pan-coronavirus immunity. <b>/CNIO</b>Image of the first Spikebody prototype. Synthetic immunology will be used as a tool to engineer pan-coronavirus immunity. /CNIO

Inés Muñoz, Head of the Crystallography and Protein Engineering Unit at CNIO, is collaborating with i+12 on a project to design a new immunotherapy technique to generate antibodies against different types of coronavirus, including the one that causes COVID-19.

The aim is to create molecules with sufficient capacity to block infection caused by any coronavirus, and which, as in the case of COVID-19, serve as treatment or prophylaxis in patients hospitalised with serious diseases.

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Interview

Marisol Soengas: "In just over 10 years, at least partial responses can be achieved in about 50-60% of melanoma patients"

Marisol Soengas. <b>/A. Garrido. CNIO</b>Marisol Soengas. /A. Garrido. CNIO

We spoke with Marisol Soengas, Head of the CNIO’s Melanoma Group, about her latest findings on how melanomas evade the immune system.

How can the immune system help us fight a genetic disease like cancer?

The immune system is the body’s internal police force that recognises foreign invaders such as viruses and bacteria, and also tumour cells. Different components of this defence battalion act on various levels. The first step is to recognise molecules on the surface of malignant cells that distinguish them from normal cells (this is done by, among others, macrophages). This process is not very efficient, because there are few reconnaissance patrols, so the second step is to recruit more immune cells into the tumour environment. The third step is to activate mechanisms of attack or destruction, and the fourth step is to eliminate these malignant cells.

This defence process as a whole is actually quite efficient, but in aggressive tumours such as melanoma, failures occur in both recognition and attack of the tumour. However, in recent years strategies (antibodies) were developed that can disable the protection mechanisms of different types of tumours. Melanomas are examples of such successful research: in just over 10 years, at least partial responses can be achieved in about 50-60% of patients. There are currently more than 3000 clinical trials underway on many other tumour types, with good results in for example lung cancer. However many patients are still resistant to therapy or suffer important side effects.

You found out that melanoma ‘tricks’ our immune system. How does it do this?

We are quite proud of our studies being published in Nature Medicine, one of the best journals in the field. Specifically we describe how melanomas not only hide from the immune system, but also they redirect its function so that, instead of being in recognition and attack mode, immune cells become infiltrators that help tumour development. We identified a protein called Midkine that mediates this switch in function. We also showed that blocking Midkine increases the response to immunotherapy in animal models and described genes associated with this reversal in patient samples. Finally, we described the immunomodulatory effects of Midkine in glioblastomas, and lung and renal carcinomas. Midkine is also altered in other pathologies, so we believe that our results will open new avenues of research in oncology.

What will be the next steps in this research?

We have very interesting studies on the effects of Midkine on different components of the immune system that will allow us to gain a better understanding of how melanomas acquire a great malignant and metastatic capacity already at very early stages of the disease. We are also pursuing pharmacological inhibitors of Midkine, which we will try to study in different experimental models.

Profile

José Luis Rodríguez Zapatero, President of the Spanish Government between 2004 and 2011, gave a talk on 15 September as part of the WISE cycle of meetings of the CNIO Office for Women in Science. Under the title Science and Politics, Rodríguez Zapatero called for the creation of a high-level commission made up of scientists, economists, thinkers and technologists who are beyond reproach, to propose projects to be funded by European recovery funds due to the effects of the COVID-19 pandemic.

To the vision of science as a way to improve life expectancy and health, the former president wanted to add the role that science plays as an element of coexistence based on principles and values. He thus highlighted equality between men and women as one of these fundamental principles and stressed that the 21st century must be decisive in favour of gender equality.

José Luis Rodríguez Zapatero (1960) obtained his law degree from the University of León. He was a member of parliament elected by the autonomous communities of León (1986-2004) and Madrid (2004-2011). From 2000 to 2012, Zapatero was Secretary-General of the Spanish Socialist Workers’ Party (PSOE). He holds honorary doctorates from the Toulouse 1 Capitole University in France (2015), the Universidad Mayor de San Andrés, Bolivia (2015), and the Universidad Autónoma de Santo Domingo, Dominican Republic (2017). He chairs the Forum for Socially Responsible Recruitment, and is a member of the Royal Board on Disability, the Board of CERMI Women, the Club of Madrid, and the International Commission against the Death Penalty. He is the author of the book The Dilemma: 600 days of vertigo, published by the Planeta publishing house in 2013.

His main actions as the head of the Government of Spain include legislative initiatives such as the Comprehensive Law against Gender Violence (2004); the law that recognizes same-sex marriage (2005); the Act on effective equality of women and men, the Historical Memory Law (2007); or the Act on Victims of Terrorism of 2011.

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