Section A : Biosketch

• EDUCATION
  
  • 1980-1984 MSc (cum laude). “Molecular analysis and chromosomal localization of the TK gene co-transfected in mouse cells with satellite DNA”, Oct. 1984. Faculty of Biology/ Department of Genetics, University of Pavia, Italy.
  • 1985-1990 PhD. “Evolution of Multigene Families: Hemoglobins and Haptoglobins”, Nov. 1, 1990. Faculty of Medicine, Department of Human Genetics, University of Leiden, The Netherlands.
• PROFESSIONAL EXPERIENCE
  
  • 1990 – 1992 post-doc at the Department of Human Genetics, University of Leiden, The Netherlands. Research Field: Molecular genetics of hereditary colon cancer.
  • 1992 visiting scientist at the Dept. of Molecular Genetics, Albert Einstein College of Medicine, Yeshiva University, New York, USA. Research Topic: Generation and Analysis of Transgenic Mouse Models for Colorectal Tumorigenesis.
  • 1992 – 1997 fellow of the Royal Dutch Academy of Science (KNAW). Research Topic: Generation and Analysis of Transgenic Mouse Models for Colorectal Tumorigenesis.
  • 1995 – 1996 visiting professor at the Dept. of Human Genetics, University of Newcastle upon Tyne, U.K. Host: Prof. John Burn.
  • 1997 – 2001 associate professor (UHD) at the Department of Human Genetics, University of Leiden, The Netherlands.
  • 2001 – 2003 full professor of “Cancer Genetics”, Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • 2003 – to date full professor of “Experimental Pathology”, Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 2017 – to date visiting professor at Zhejiang University (ZJU), Hangzhou, China.
• FELLOWSHIPS AND AWARDS
  
  • 1985 Short-term European Molecular Biology Organization (EMBO) fellowship.
  • 1992 Fellow of the Royal Dutch Academy of Sciences (KNAW).
  • 2002 Elected as member of the European Molecular Biology Organization (EMBO)
  • 2003 NWO (Dutch Research Council) VICI-laureate.
  • 2004 Frieda den Hertog Jager Prize. Dutch Society of Gastroenterology.
  • 2007 Ronald Raven Prize, BASO – The Association For Cancer Surgery, London, UK.
  • 2016 MD Anderson Cancer Center, Houston, TX, USA. Distinguished Lecturer Science in Medicine.
  • 2016 Chinese University of Hong Kong, China. Honourable Speaker Cancer: from Biology to Treatment

• FUNDING ID (since 2000)

  • 2001-2004 The role of base excision repair in intestinal tumor initiation and progression. MWO 04-21. Maag, Lever, Darm Stichting. MLDS
  • 2002-2006 Microarray analysis of factors determining apoptosis in human rectal cancers. RUL2002-2733. KWF Dutch Cancer Society
  • 2003-2008. Modulation of stem cell differentiation by Apc/-catenin signal transduction. 016.036.636. NWO VICI
  • 2004-2008 Stem Cells in Development and Disease. 03038. Senter/BSIK (www.stemcells.nl)
  • 2005-2009 Cross-talk between receptor tyrosine kinases and -catenin signalling during tumor initiation and progression. DDHK 2005-3299. KWF Dutch Cancer Society
  • 2007-2011 Identification of novel kinases involved in cancer-relevant processes. T3-103. Top Institute Pharma
  • 2007-2011 Distinct dosages of Wnt/-catenin signaling levels underlie colon and breast cancer stemness. EMCR 2007-3740. KWF Dutch Cancer Society
  • 2007-2010 Migrating Cancer Stem Cells in breast and colon cancer. 37297. EU FP6 (www.mcscs.eu).
  • 2008-2012 TuMIC: an integrated concept of tumor metastasis. 201662. EU FP7 (http://www.umm.uni-heidelberg.de/inst/cbtm/mbio/tumic/)
  • 2008-2012 Cross-talk of sex hormones and Wnt/-catenin signaling in endometrial cancer. EMCR 2008-4056. KWF Dutch Cancer Society
  • 2010-2014 Netherlands Institute for Regenerative Medicine (NIRM). The Life Sciences & Health innovation program of the Dutch government. www.nirm.nl; www.regeneratieve-geneeskunde.nl
  • 2010-2011 Erasmus Stem Cell Institute (ESI). (www.erasmusmc.nl/medical_genetics/esi/).
  • 2012-2014 Paneth cells in intestinal cancer: supporting act or main feature? EMCR 2012-5473. KWF Dutch Cancer Society
  • 2014-2018 Cell of Origin and Cancer Stem Cells in Ovarian Cancer. Erasmus MRACE funds.
  • 2015-2019 Early alterations of the intestinal stem cell niche underlie sporadic colon cancer driven by “Western style” dietary factors. WCRF 1181. World Cancer Research Funds International.
  • 2016-2020 EpCAMlow cancer stem cells: the culprit of liver metastasis in colon cancer? FP-1508. MLDS (Dutch Gastroenterology Society).
  • 2016-2020 The role of Wnt signaling in high-grade serous ovarian cancer stemness and therapy resistance.. EMCR 2015-8090. KWF Dutch Cancer Society
  • 2018-2022 Secretory Paneth-like cells as the origin of intestinal cancer. EMCR 2018-11407 KWF Dutch Cancer Society
• INSTITUTIONAL RESPONSIBILITIES and COMMISSIONS OF TRUST
  
  • 1999 – 2011 Member of the steering group of the CAPP2 study, a multi-national genetic trial of Aspirin among FAP and HNPCC patients. http://www.capp3.org/
  • 2000 – 2006 Member of the Scientific Board Telethon Italia
  • 2003 – 2013 Chairman of Experimental Pathology and Deputy Head of the Dept. of Pathology, Erasmus MC, Rotterdam, The Netherlands
  • 2003 – to date Communicating Editor of Human Mutation.
  • 2006 Member of the EMBO Focus Group on Stem Cell Research
  • 2007 – 2012 Member of the Scientific Board of the Dutch Cancer Society
  • 2007 Member of the Research Council of Norway project evaluation commission
  • 2008 – 2012 Vice-chairman of the Fundamental Research commission of the Dutch Cancer Society
  • 2008 – 2010 Member of the Editorial Board of PathoGenetics
  • 2009 – 2015 Member of the Board of Directors of the postgraduate research school Molecular Medicine, Erasmus MC, Rotterdam, The Netherlands.
  • 2015 – 2016 Guest Associate Editor at PLOS Genetics.
  • 2015 – 2021 Member of the European Research Council Starting Grant commission (LS3)
• Scientific Leadership Profile
  • During my PhD (prof. L. Bernini, University of Leiden, 1985-1990), I laid the basis for the elucidation of the genetic basis of thalassemias in The Netherlands where an extremely heterogeneous spectrum of ethnical populations from various regions throughout the malaria belt is present. This required a highly sensitive and comprehensive detection method covering multiple genes, and capable of detecting both point mutations as well as genomic rearrangements. The large number of defects identified allowed the elucidation of the molecular and genetic basis of these conditions in The Netherlands and formed the basis for carrier detection, pre- and post-natal diagnosis, and the application of preventive measures to reduce morbidity and mortality among several ethnical groups which comprise approx. 20% of the Dutch population. Selected publications: Genomics 1990;8(4):732-5; Blood 1991;77(4):861-7; Hum Mutat 1994;3(2):83-94.
  • During my first post-doctoral experience (prof. P.M. Meera Khan, University of Leiden, 1990-1992), I worked at hereditary colorectal cancer syndromes and in particular FAP (familial adenomatous polyposis) and Lynch syndrome (LS or HNPCC). The knowledge and methods acquired and developed during my PhD allowed their rapid application to the genes responsible for these conditions (APC and MYH for FAP and MSH2, MLH1, MSH6 and PMS2 for LS). This, combined with the unique familial colorectal cancer registries previously established in The Netherlands, led to the rapid elucidation of the genetic basis of these hereditary syndromes and the establishment of accurate genotype-phenotype correlations to allow pre- and post-natal diagnosis and presymptomatic predictions of their clinical courses. In fact, these findings were of a much wider societal impact, as the mutation spectrum among Dutch hereditary colorectal cancer kindreds contributed to the elucidation of the genetic basis of FAP and LS worldwide. Exemplary illustrations of this are represented by the identification of a US founder mutation in the MSH2 gene estimated to be responsible for 25% of the LS cases in the United States, and the description of a novel syndrome, hereditary desmoids disease (HDD) in a British family, subsequently validated in several European countries and in the US. Selected publications: Nat Genet 1998;20(4):326-8; N Engl J Med 1998;339(8):511-8; Nat Genet 1999;23(2):142-4; Am J Hum Genet 2003;72(5):1088-100.
  • A further extension of my post-doctoral fellowship was provided by the Royal Netherlands Academy of Arts and Sciences (KNAW; 1992-1997. Dept. of Human Genetics, University of Leiden, The Netherlands and Dept. of Molecular Genetics, Albert Einstein College of Medicine, New York, USA) and resulted in the generation of unique preclinical mouse models for FAP and LS, and for intestinal cancer in general. In particular, the applicant developed the very first knock-out model for the mouse Apc gene (Apc^1638N/+), in addition to several others which provided further confirmation of the above mentioned genotype-phenotype correlations observed in clinical samples and largely contributed to the elucidation of the molecular and cellular basis of tumor onset in the GI tract. These animal models have been employed by the scientific community at large and are still regarded as unique tools for basic and translational cancer research worldwide. Selected publications: PNAS USA 1994;91(19):8969-73; Gastroenterology 1998;114(2):275-83; Genes Dev 1999;13(10):1309-21; Gastroenterology 2000;119(4):1045-53; Trends Mol Med 2001;7(8):369-73; Oncogene 2006;25(13):1841-51; Gastroenterology 2006;131(4):1096-109. Carcinogenesis 2010;31(5):946-52; Gut 2011; 60(9):1204-12.
  • During a one-year visiting professorship at the University of Newcastle, UK (1995-1996) and in close collaboration with prof. John Burn, a unique genetic trial was established and implemented aimed at the evaluation of the preventive role of Aspirin and Amylose (resistant starch) in HNPCC and FAP. The CAPP studies (Concerted Action for the Prevention of Polyps; http://research.ncl.ac.uk/capp2/) not only demonstrated the preventive role of Aspirin in LS but also opened new avenues to explore aspirin’s role as a coadjuvant in cytotoxic cancer therapy. The latter is currently being further investigated in collaboration with the LUMC (dr. G.I. Liefers) and has led to the first (ongoing) prospective trial where aspirin is randomized in colon cancer patients. Selected publications: N Engl J Med 2008;359(24):2567-78. Lancet 2011; 378(9809):2081-7. Br J Cancer 2012;106(9):1564-70. JAMA Intern Med 2014 Mar 31 [Epub ahead of print].
  • The above studies spanning from basic to translational and clinical research allowed me to integrate the results towards the elucidation of the molecular and cellular basis of intestinal cancer. Highlights of this comprehensive research strategy are the “just-right model” to redefine Knudson’s the two-hit hypothesis for the APC tumor suppressor gene; the relevance of dosage in Wnt signaling and its consequence for tumor susceptibility; the APC gene as primary cause of chromosomal instability in colorectal cancer; and the role of Wnt in defining self-renewal and differentiation potential of stem cells. These results also led to the prestigious VICI grant from the Dutch Research Council (NWO) to study stemness in homeostasis and cancer at a time when the current cancer stem cell “hype” had not emerged yet. The VICI recognition also coincided with my first professorial chair (“Cancer Genetics”, University of Leiden; 2001). Shortly after (from 2003 on), I moved my research group from Leiden to the Erasmus University Medical Center in Rotterdam where I took the chair of “Experimental Pathology” at the Dept. of Pathology. The move to Rotterdam allowed me to place my research in a more multi-disciplinary and high-standard environment where to implement a novel research line on stem cells in homeostasis and cancer. Selected publications: Nat Rev Cancer 2001;1(1):55-67; Nat Cell Biol. 2001;3(4):433-8; Hum Mol Genet 2002;11(13):1549-60; Nat Genet 2002;32(4):594-605; Am J Pathol 2007;170(1):377-87; PLoS Genet 2009;5(7):e1000547; Cell Stem Cell 2011;9(4):345-56; PLoS Genet. 2013;9(5):e1003424.
  • During the last 10 years, the focus of my research at the Erasmus MC has been centered on phenotypic plasticity in homeostasis, response to tissue insults, and cancer. Phenotypic plasticity, defined as the ability of one genotype to produce more than one phenotype when exposed to different environments, is regarded as the most clinically relevant hallmark of epithelial cancers as it allows tumor cells to locally disseminate into the surrounding stromal microenvironment and to survive the long-distance trip to the metastatic site. In our most recent study, we identified a subpopulation of colon cancer cells endowed with phenotypic plasticity that underlies distant metastasis, and elucidated the underlying molecular mechanisms by single-cell RNAseq analysis. (eLife 2021 10:e61461).
    
    Next to its key role in metastasis, my interest in this research area has been triggered by the dogma-breaking hypothesis according to which phenotypic plasticity may not be limited to stem and progenitor cells but also feature allegedly post-mitotic and terminally differentiated cell types in the context of tissue injury. We have proved this fundamental concept with an unbiased approach for the identification and characterization of label-retaining cells (LRCs) in the intestinal epithelium, i.e. long-lived quiescent cells capable of re-entering the cell cycle upon whole body gamma-irradiation (PLoS One 2012; 7(6):e38965.). Following up on this original observation, we hypothesized that the Paneth cells may contribute to the regenerative response following acute inflammation, and as such play a role in IBD. By employing the DSS mouse model in combination with lineage tracing and organoid technology, Paneth cells where shown to de-differentiate to acquire multipotential stem-like features capable of giving rise to all epithelial lineages of the adult small intestine (Cell Rep 2018; 24(9):2312-2328.e7). The cascade of transcriptional changes caused by inflammation in Paneth cells culminate in Wnt activation as a main driver of stemness.
    
    In 2011, the Clevers laboratory elucidated the role of PCs as niche cells that secrete essential ligands and growth factors to support Lgr5+ stem cells. Based on this seminal study, we developed the organoid reconstitution assay (ORA) for the ex vivo functional analysis of Paneth and Lgr5+ ISCs (J Vis Exp 2017; 129:56329). By taking advantage of ORA, we identified the Paneth-specific secreted phospholipases A2 as intestinal stem cell niche factors with context-dependent functions in homeostasis, inflammation, and cancer (Cell Stem Cell 2016; 19(1):38-51). The same study led to the identification of colonic Paneth-like cells with similar niche function as in the small intestine.
    
    The stem and niche function of Lgr5+ and Paneth cells respectively, are reflected by a striking metabolic dichotomy, reported in a collaborative study with the Burgering’s laboratory (Utrecht, NL). While Lgr5+ ISCs display high mitochondrial and OXPHOS activity, glycolysis represents the metabolic program characteristic of Paneth cells. Inhibition of mitochondrial activity in Lgr5+ ISCs or of glycolysis in PCs strongly affect overall stem cell self-renewal and differentiation (Nature 2017; 543(7645):424-427).
    
    In parallel to the intestinal crypt in homeostasis, inflammation, and cancer, phenotypic plasticity is also central to my laboratory’s second main research line on cancers of the oral cavity and in particular of the tongue. The mammalian tongue is among the most regenerative organs though the cellular and molecular mechanisms underlying regulation of its stem cell niche in homeostasis and tissue injury are yet poorly characterized. The majority of the tumors of the oral cavity occurs in the tongue, the main treatment for which is still represented by surgery followed by postoperative (chemo/radio-)therapy, with an overall poor prognosis. In collaboration with Peter Verrijzer’s laboratory at the Erasmus MC, we uncovered the competitive antagonism between two main chromatin remodeling complexes, NuRD and SWI/SNF, in the regulation of epithelial-to-mesenchymal transition (EMT) in oral cancer cells (Cell Rep 2017; 20(1):61-75). The same competition regulates squamous cell differentiation in the lingual stem cell niche during homeostasis. Our most recent and yet unpublished epigenomics and functional analysis of genetically modified human cancer cell lines and mouse organoids revealed that the NURD-SWI/SNF ‘tug-of-war’ controls, next to EMT, major inflammatory signaling pathways such as NFkB, IL6/JAK/STAT3, and IL2/STAT5. This original and exciting observation points once again to the functional interaction between stemness and inflammation, with potential connections to IBD and Crohn’s disease.