Pr. Dr. Cédric Blanpain Stem Cells and their connection to Cancer Progress report

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1 Pr. Dr. Cédric Blanpain Stem Cells and their connection to Cancer Progress report The Prof. MD. Cédric Blanpain is a world leader in the field of stem cells and cancer. He has also been elected Outstanding Young Investigator Award by the International Society of Stem Cell Research and has been selected by the most prestigious Nature journal among the 10 world-leading researchers that mattered in Prof. MD. Cédric Blanpain studies stem cells during development and tries to understand how the different cells start acquiring their cell identity, how the adult stem cells enable tissue renewal throughout the life of the animals and how the stem cells mediate tissue repair following injuries. His laboratory also studies whether stem cells act as the cancer cell of origin and whether cancer stem cells fuel tumor growth and mediate resistance to anti-cancer therapy. A stem cell is like the mother of all cells it gives birth to other cells that allow tissues to grow and differentiate into the cell lineages that form our different tissues. There are several types of stem cells: the pluripotent embryonic stem cells, the embryonic progenitors, the adult stem cells, and the cancer stem cells. Cardiovascular progenitors Cédric Blanpain has identified the Mesp1 gene as the molecular switch that allows the transformation of pluripotent stem cells into a cardiac cells. This has been an important step in the understanding of the cardiac morphogenesis with important implications for regenerative medicine (Bondue A., Cell Stem Cell, 2008 and Journal of Cell Biology, 2011). Cédric Blanpain decides to go further into the topic of these cardiovascular progenitors. He recruits new researchers to mark cardiac stem cells at the very beginning of their formation and succeeds in tracing the entire genealogy of the formation of the heart, finding the embryonic origin of the cardiac cells. This is how he shows that the heart is made of spare parts, the cardiovascular progenitors are indeed born at different moments and differentiate themselves into different cardiac cells and contribute to the formation of the different parts of the heart (Lescroart F., Nature Cell Biology 2014) Fondation ULB - Fondation d utilité publique - Avenue Franklin D. Roosevelt 50 CP 129 B Bruxelles 1

2 Pr. Dr. Cédric Blanpain - Progress report With the same researchers, he then succeeds, by clonal tracing, at determining how many cardiac progenitors are needed to make a heart, that is to say about 250 cardiovascular progenitors expressing Mesp1. This finding made the cover of Cell Report at the beginning of this year. This technique allows to mark stem cells and follow their progeny and follow the dynamic of stem cell s proliferation, how it divides and how many progenies it will make. This technique allowed him to make paradigm shifts in the understanding of the different skin and mammary gland tissues. The cover shows a pixelated confocal analysis. Every color represents a unique cardiac progenitor. Chabab S., Cell Reports, 2016 Thanks to this technique, his lab could also understand how the skin renews itself all life The stem cells migrate long distances to repair the hole (inside the dotted line) that was made in the tissue. Nature, Adult stem cells Cédric Blanpain studies the adult stem cells and how they control tissue renewing and repair. His lab particularly studies two tissues, the skin and the mammary gland, for two reasons: they are important tissues, key to the survival of the animals and because the most frequent cancers arise from these tissues. It is estimated that one person out of five will develop a skin cancer and that one woman out of six will one day develop breast cancer. long and he showed that some relatively quiescent cells were activated and greatly participated to tissue repair (Mascré G., Nature, 2012). Cancer stem cells One of the essential questions that Cédric Blanpain is addressing concerns the origin of cancers. Scientists knew for a very long time that cancers were linked to bad genes and that one had to accumulate a number of these bad genes in the progeny of a single cell. Cédric Blanpain explains that his laboratory masters the lineage tracing techniques. Lineage tracing offers the possibility to activate fluorescent proteins in tissue, allowing cells to be labeled permanently by fluorescent protein. But which are the cells accumulate these mutations were not known? 2

3 Pr. Dr. Cédric Blanpain - Progress report Cédric Blanpain and his team have now uncovered the cellular origin of several important skin cancers. He found that all the cells are not equivalent to initiate tumor formation. Only certain cells are capable of changing identity and developing a cancer after they express the bad genes responsible for tumor initiation. His lab showed that current view of cancer cell of origin based on the similarity between the cells presented in normal tissue and tumor cells are very often misleading because the cells that undergo transformation change their identity during tumor initiation, and begin to express markers not expressed by normal cells (Youssef K.K., Nature Cell Biology, 2010). He continues now this project by collaboration with a pharmaceutical spin-off that is developing molecules that block efficiently the pathway they identified as critical for basal cell carcinoma initiation. His lab has recently discovered that the elimination of the Sox9 gene prevent basal cell carcinoma progression. Sox9 gene is also expressed in most human cancers and will help create new therapeutic strategies in order to stop tumour progression and invasion (Larsimont J.C., Cell Stem Cell, 2015). Sox9 and the tumour invasion Cell Stem Cell, 2015 The identification of the cancer cell of origin and the change of cell identify that accompanied tumor initiation was a real paradigm shift in the field of cancer biology. The study on the identification of the cells responsible for basal cell carcinomas, the most frequent human cancer, has become a highly cited paper that made the cover of Nature Cell Biology, 2010 Cédric Blanpain explains that his lab is currently exploring if the stem cells and the progenitors are both responsible to basal cell carcinoma formation. For now, the results show that only the stem cells are involved. They published this paper in July 2016 in Nature (Sánchez-Danés, Nature, 2016). Breast cancers One of the main topics followed by his lab is the study of the mammary gland and its cancers, which are heterogeneous and associated with good as well as bad prognosis. Following this path, his lab discovers the molecular mechanisms that lead to the initiation of basal cell carcinoma (Youssef K.K., Nature cell biology, 2012) and leading to the identification of a small molecule inhibitor capable of blocking tumor formation. His team discovered the existence of two very distinct stem cell subtypes (basal and luminal) that allow the renewing of two types of cell lineages that make up the mammary gland. This research open new ways to study the cells responsible for different subtypes of breast cancers, an essential and still unresolved question (Van Keymeulen A., Nature 2011). 3

4 Pr. Dr. Cédric Blanpain - Progress report This research has recently led to the discovery of the origin of breast cancers induced by the PIK3CA gene. This study confirms the relevance of the animal model in the understanding of human cancers (Nassar D., Nature Medicine, 2015). The study also showed that the PIK3CA and p53 genes mutations (the most frequently mutated genes in breast cancer) induce very different types of tumour depending on their cell of origin. Mutation in luminal cells usually results in more aggressive tumours (Van Keymeulen A., Nature 2015). Tumour resulting from the PIK3CA and p53 mutations Nature 2015 Understanding how cancers grow, once formed In the same framework of squamous cell carcinoma, the lab has studied skin cancer stem cells on genetically modified mice. The research has shown that inhibition of Twist1 gene reduces drastically the formation of tumours and that Twist1 gene was essential for tumour maintenance and regulation of cancer stem cells. This discovery made the cover of Cell Stem Cell journal. (Beck B., Cell Stem Cell 2015) His lab is now trying to understand why the mammary gland produces different subtypes of cancers. Could there finally be, among the luminal stem cells, not one type of stem cell but several subtypes of luminal stem cells, each giving a particular type of cancer? Cédric Blanpain assures that his researchers are on the right track but need more funding to get there. This new contribution has proven to be a twist in our understanding of tumourigenesis induced by Twist1. Cell Stem Cell 2015 Validating the animal model Within the squamous cell carcinoma, we have until recently ignored the relevance of the mouse model. Still within the squamous cell carcinoma framework, his team demonstrated the importance of the transcription factor Sox2 in the initiation and the growth of skin cancers as well as in the regulation of cancerous stem cells. Cédric Blanpain s lab has tackled the sequencing of the mouse tumours and has discovered that the same genes were mutated in human and mouse squamous cell carcinoma. The researchers have shown the importance of these cells for tumour growth by eliminating these cancer cells in their natural environment with a genetic system (Boumahdi S. Nature, 2014). 4

5 Pr. Dr. Cédric Blanpain - Progress report After one week of treatment, the tumours have dramatically shrunk. This shows the therapeutic potential of targeting cancerous stem cells. Nature 2014 Tumour Relapse Cédric Blanpain explains that when one gives chemotherapy or radiotherapy to a patient, one can sometimes see a great shrinking of the tumour that can unfortunately be followed by a relapse. A potential cause of tumours relapse could be that we kill everything but the cancer stem cells. His lab discovered a subtype of cell resistant to chemo and radiotherapy. Cédric Blanpain is sure that they have identified the molecular mechanism of this resistance. He thinks that within the next few months, he will be able to announce this great new discovery. Metastasis Cédric Blanpain explains that most of the time it is not the primary tumour that kills the patient but cells that escape the primary tumour and travel to the lungs, brain, liver, or bones. Cédric Blanpain thinks that they are well advanced in that particular field but that complementary funding is necessary to keep up this promising project. Personalized Medicine Cédric Blanpain s lab does fundamental research but wants to transfer its discoveries to clinical practice. One of the dreams that Cédric Blanpain shares with the researchers of the ULB Cancer Research Center is to be able to offer all ULB hospital s patients the possibility of taking samples of their tumour, molecularly characterize them, classify them and try on these transplanted tumours the most adapted treatments. This project currently needs five full-time researchers responsible for collecting tumour samples from patients at the Erasme Hospital thanks to funding from the Fonds Erasme (300K /year for 6 years). Despite this, Cédric Blanpain explains that this budget is way insufficient and that the project needs massive funding to create the biggest living biobank of tumours in Belgium and in Europe with all tumors being sequenced for the research of mutations. In this matter, Cédric Blanpain thinks the generosity of the Fondation ULB s sponsors might make a difference. Part of his team tries to discover which are the cell populations that escape the primary tumour and colonize other body areas. 5

6 Conclusion The Prof. MD. Cédric Blanpain leads a team of about forty brilliant, committed and effective PhD researchers, postdocs, and specialized technicians from around the world. Cédric Blanpain s lab achieved a steady speed that was made possible by his public, private, national and international financial supports. The annual operational cost of his laboratory is 3,6M Furthermore, Cédric Blanpain explains that he continuously seeks funding to allow his researchers to work (reagents needed for the realization and the analysis of the experiments) or to ensure the maintenance of the machines his lab uses. Staff (38) Reagents ( /researcher) Equipment maintenance ULB management costs 2M /year 1,2M /year 100K /year 300K /year He notices that the public funding that allowed to launch his lab has dramatically decreased. For example, his FNRS fundings (Fonds National de la Recherche Scientifique) decreased by 75%. In his lab, the FNRS can now only finance one grant per four year and does no longer finance the purchase of large piece of equipment. total 3,6M /year Despite the fact that his research meets a great success, Cédric Blanpain explains that his lab is constantly looking for new funding. Indeed, aside from the specific projects that require important funding like his project regarding the mechanisms regulating metastasis (1M ), his project on the resistance to treatment (1M ), the personalized medicine project (500K /year), his lab also needs to purchase new equipment (1,5M ). Cédric Blanpain concludes by saying that without philanthropy, his lab couldn t work at this pace. He mentions that the Fonds Baillet-Latour is nowadays the institution that grants him with the largest financial support, even larger than the support from European Research Council (ERC). Finally, he heartily thanks his sponsors, whose generosity allowed him to finance specific research projects, to hire qualified staff, to update a part of his lab facilities or the partial funding of an administrative support that allows him to save precious time for his research. Le laboratoire du Pr. Dr. Cédric Blanpain est soutenu notamment par: 6

7 Pr. Dr. Cédric Blanpain s Lab Funding requirements 1. Mecanisms regulating metastasis Personnel 1M (5x ) 3. Personalized medicine project Personnel /an 1 post-doc 1 post-doc 1 technician 1 technician Consumables 400K Consumables 100K Mice housing (/an) and Sequencing (3) Mice housing (15K ), Transgenic mice generation and importing (15K ), Molecular biology reagents (20K ), Cell sorting and confocal imaging (15K ), Publications (5K ), Travel and conferences for the post-doc (5K ) total 500K /year total 200K /year 4. New equipments 1,5M 2. Resistance to treatment Animal housing - cages 2 Personnel 1M (5x ) Confocal microscopy 5 Sequencer 700K 1 post-doc total 1,5M 1 technician Consumables 100K / Mice housing (15K ), Transgenic mice generation and importing (15K ), Molecular biology reagents (20K ), Cell sorting and confocal imaging (15K / an), Publications (5K ), Travel and conferences for the post-doc (5K ) For detailed information on a specific project, please contact Mr. Luc Nguyen: total 200K /year Fondation ULB - Fondation d utilité publique Avenue Franklin D. Roosevelt 50 CP129 B-1050 Bruxelles tél + 32 (0) fondation@ulb.ac.be 7

8 SUPPORTING SCIENCE Cédric Blanpain, born in Medical Doctor, PhD in Medical Sciences, Board Certified in Internal Medicine (Université libre de Bruxelles). He did his post-doc in the laboratory of Pr. Elaine Fuchs at the Howard Hughes Medical Institute (Rockefeller University). Cédric Blanpain is now full Professor at the Université libre de Bruxelles and vice-director of the ULB Cancer Research Center. Pr. M.D. Cédric Blanpain is recipient of many prestigious fellowships and awards, notably: European Research Council (ERC) Starting et Consolidator grants, Nature s Top 10 of the Scientists who mattered, Outstanding Young Investigator Award International Society of Stem Cell Research, member of the European Molecular Biology Organization, Investigator of the Walloon Excellence in Lifesciences and Biotechnology grant, Liliane Bettencourt Award for Life Sciences, member of the Belgian Royal Academy of Medicine and Academia Europaea. The mission of the Fondation ULB is to financially support innovative research projects at the Université Libre de Bruxelles (ULB) and to help researchers at the forefront of their discipline to achieve significant scientific progress. The Fondation ULB is Belgian nonprofit institution, created by Royal decree and can receive taxdeductible gifts from corporations/foundations/ private individuals from Belgium, Europe and the US. The scientific projects supported by the Fondation ULB were selected on one criteria: excellence. All projects were reviewed by the Research Council and the Academic Council of the Université Libre de Bruxelles and by international scientific committees (European Research Council, Pôle d attraction interuniversitaire and Action de Recherche Concertée). Fondation ULB Fondation d utilité publique The Université libre de Bruxelles (ULB) is an international and complete teaching and research university with an academic hospital (ULB-Erasme). The ULB gathers more than 4000 researchers, professors, PhDs and specialized lab technicians. The ULB has been awarded with many prizes and awards including: 4 Nobel Prizes (Physics, Physiology or Medicine, Chemistry), 1 Fields Medal, 2 Abel Prizes, 3 Wolf Prizes, 1 Balzan Prize, 20 European Research Council Grants, 29% of Francqui Prizes (the highest honour in Belgian scientific prizes), 50% of the Five-yearly FNRS Prizes. Avenue Franklin D. Roosevelt 50 CP129 B-1050 Bruxelles Bank ACCOUNT for your tax-exempt GIFTS: IBAN BE Info: fondation@ulb.ac.be