Date and place of birth : Sept. 16, 1960; Cagliari, Italy.
Nationality : Italian and Dutch.
Section A : Biosketch
- 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 – to date 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 (Apc1638N/+), 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 years the focus of my research has been centered on the cancer stem cells concept not only in intestinal neoplasia but also in mammary, endometrial and esophageal cancer. In the particular case of the intestinal (cancer) stem cell niche, my research has been focusing on Paneth cells because of their dual role as niche cells which secrete niche-essential ligands and growth factors such as Wnt3a and phospholipases, and as quiescent stem cells which are activated upon tissue insults (e.g. inflammation). Paneth cells reside exclusively in the small intestine and as such are apparently irrelevant to colon cancer. However, in chronic inflammatory conditions such as ulcerative colitis (inflammatory bowel syndromes, IBD), metaplastic Paneth cells are present in the normal and tumor-associated colonic mucosa, allegedly to support Lgr5-expressing cancer stem cells. Our latest and most promising line of research is aimed at the identification and characterization of these Paneth-like cells in the colon and of different members of the secreted phospholipases (PLA2G2A and PLA2G10) as stem cell niche factors and genetic modifier of IBD-associated colon cancer. Selected publications: PLoS One. 2012;7(7):e40691. PLoS One. 2012;7(6):e38965. Cell Commun Adhes. 2011 Jun;18(3):33-44. EMBO Rep. 2011 Jun;12(6):483-4. Cell Stem Cell. 2016, in press.
Section B : Track-record
Selected publications, as first and senior author
- Schewe M, Sacchetti A, Schmitt M, Fodde R. The Organoid Reconstitution Assay (ORA) for the Functional Analysis of Intestinal Stem and Niche Cells. J Vis Exp. 2017 Nov 20;(129).
- Mohd-Sarip A, Teeuwssen M, Bot AG, De Herdt MJ, Willems SM, Baatenburg de Jong RJ, Looijenga LHJ, Zatreanu D, Bezstarosti K, van Riet J, Oole E, van Ijcken WFJ, van de Werken HJG, Demmers JA, Fodde R, Verrijzer CP. DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells. Cell Rep. 2017 Jul 5;20(1):61-75.
- Fodde R, Schmitt M, Schewe M, Augenlicht LH. Modelling western dietary habits in the mouse: easier said than done. Hepatobiliary Surg Nutr. 2017 Apr; 6(2):138-140.
- Rodríguez-Colman MJ, Schewe M, Meerlo M, Stigter E, Gerrits J, Pras-Raves M, Sacchetti A, Hornsveld M, Oost KC, Snippert HJ, Verhoeven-Duif N, Fodde R, Burgering BM. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature. 2017 Mar 16;543(7645):424-427.
- Schewe M, Franken PF, Sacchetti A, Schmitt M, Joosten R, Böttcher R, van Royen ME, Jeammet L, Payré C, Scott PM, Webb NR, Gelb M, Cormier RT, Lambeau G, and Fodde R. Secreted phospholipases A2 are stem cell niche factors with distinct roles in homeostasis, inflammation and cancer. Cell Stem Cell, 2016 Jul 7;19(1):38-51.
- van der Zee M, Sacchetti A, Cansoy M, Joosten R, Teeuwssen M, Heijmans-Antonissen C, Ewing-Graham PC, Burger CW, Blok LJ, Fodde R. IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden. Cancer Res. 2015 Sep 1;75(17):3608-22.
- Atlasi Y, Noori R, Gaspar C, Franken P, Sacchetti A, Rafati H, Mahmoudi T, Decraene C, Calin GA, Merrill BJ, Fodde R. Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation. PLoS Genet. 2013 May;9(5):e1003424. doi:10.1371/journal.pgen.1003424. Epub 2013 May 2. PubMed PMID: 23658527; PubMed Central PMCID: PMC3642041.
- Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M, Fibbe WE, van Dongen JJ, Fodde R*, Staal FJ. Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell. 2011 Oct 4;9(4):345-56. doi: 10.1016/j.stem.2011.07.017. PubMed PMID: 21982234.
- Gaspar C, Franken P, Molenaar L, Breukel C, van der Valk M, Smits R, Fodde R. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet. 2009 Jul;5(7):e1000547. doi: 10.1371/journal.pgen.1000547. Epub 2009 Jul 3. PubMed PMID: 19578404; PubMed Central PMCID: PMC2697381.
- Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol. 2007 Apr;19(2):150-8. Epub 2007 Feb 16. PubMed PMID: 17306971.
- Kielman MF, Rindapää M, Gaspar C, van Poppel N, Breukel C, van Leeuwen S, Taketo MM, Roberts S, Smits R, Fodde R. Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling. Nat Genet. 2002 Dec;32(4):594-605. Epub 2002 Nov 11. PubMed PMID: 12426568.
- Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001 Oct;1(1):55-67. Review. PubMed PMID: 11900252.
- Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, van Es JH, Breukel C, Wiegant J, Giles RH, Clevers H. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol. 2001 Apr;3(4):433-8. PubMed PMID: 11283620.
- Smits R, Ruiz P, Diaz-Cano S, Luz A, Jagmohan-Changur S, Breukel C, Birchmeier C, Birchmeier W, Fodde R. E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice. Gastroenterology. 2000 Oct;119(4):1045-53. PubMed PMID: 11040191.
- Wijnen J, de Leeuw W, Vasen H, van der Klift H, Møller P, Stormorken A,Meijers-Heijboer H, Lindhout D, Menko F, Vossen S, Möslein G, Tops C, Bröcker-Vriends A, Wu Y, Hofstra R, Sijmons R, Cornelisse C, Morreau H, Fodde R. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999 Oct;23(2):142-4. PubMed PMID: 10508506.
- Smits R, Kielman MF, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S, Hofland N, van Dijk J, White R, Edelmann W, Kucherlapati R, Khan PM, Fodde R. Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev. 1999 May 15;13(10):1309-21. PubMed PMID: 10346819; PubMed Central PMCID: PMC316713.
- Wijnen J, van der Klift H, Vasen H, Khan PM, Menko F, Tops C, Meijers Heijboer H, Lindhout D, Møller P, Fodde R. MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet. 1998 Dec;20(4):326-8. PubMed PMID: 9843200.
- Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Møller P, Fodde R. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med. 1998 Aug 20;339(8):511-8. PubMed PMID: 9709044.
- Smits R, van der Houven van Oordt W, Luz A, Zurcher C, Jagmohan-Changur S, Breukel C, Khan PM, Fodde R. Apc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts. Gastroenterology. 1998 Feb;114(2):275-83. PubMed PMID: 9453487.
- Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PubMed PMID: 8940264; PubMed Central PMCID: PMC1914868.
- Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B, Breukel C, Alt E, Lipkin M, Khan PM, et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA. 1994 Sep 13;91(19):8969-73. PubMed PMID: 8090754; PubMed Central PMCID: PMC44728.
Complete publication list.