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Epithelial Stem Cells

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Nick BARKER

Nick obtained his PhD from Reading University, UK in 1996. He joined the group of Professor Hans Clevers in Utrecht the same year to investigate the role of the Wnt signaling pathway in intestinal development and cancer. Nick's early achievements included deciphering the role of the TCF family of HMG box transcription factors in controlling expression of target genes regulated by the Wnt signal transduction pathway. This work led to the demonstration that deregulation of this signalling pathway leads to constitutive activation of TCF/β-catenin target genes, which is the initiating event in colon carcinogenesis.

In 2001, he joined a Biotech company co-founded by Hans Clevers (Semaia Pharmaceuticals), where he worked as a senior scientist developing small molecule inhibitors of the TCF/β-catenin protein complex as candidate colon cancer therapeutics. In 2006, he rejoined Hans Clevers group as senior staff scientist, where his most notable recent achievements have been the identification of the Wnt target gene Lgr5 as a unique marker of adult stem cell populations in various organs, including the intestine, skin and stomach. This work also led to the discovery that the intestinal Lgr5 stem cells are the cell-of-origin of colon cancer and revealed Lgr5 as a candidate marker of cancer stem cell populations.

In 2010, Nick joined the IMB as Senior Principal Investigator and became a Research Director in 2015, where he continues to focus on the role of Lgr5 adult stem cells in epithelial renewal and cancer in organs including stomach and ovary. Nick also holds a visiting professorship at the Center for Regenerative Medicine (CRM) at Edinburgh University and is an associate principal investigator with EuroSyStem.

The availability of robust cell-surface markers for identifying and isolating epithelial stem cells is essential for studying both their normal in-vivo function during tissue renewal and for evaluating their contribution to cancer. Such markers are also invaluable for facilitating purification of these stem cell populations for therapeutic applications.

The Wnt target gene Lgr5, an orphan G-protein-coupled receptor, has been shown to mark adult stem cells in a variety of adult organs, including the intestine, skin, stomach, kidney and mammary gland. In the intestine, Lgr5 stem cells are responsible for initiating cancer following mutation. The presence of Lgr5-expressing cells in human cancers of the gastrointestinal tract has also led to speculation that Lgr5 marks a population of cancer stem cells.

Nick Barker's group will employ genetic mouse models and ex-vivo organoid culture methods to dissect the role of Lgr5 stem cells in epithelial self-renewal and cancer of various organs, including the stomach and ovary. The ultimate goal is to harness the regenerative capacity of these adult stem cells for therapeutic use, as well as developing ways of blocking the cancer-promoting activities of mutated Lgr5 stem cells.

To achieve this, we will employ the following approaches:

1) In-vivo lineage tracing using the Lgr5-EGFP-ires-CreERT2 mouse model in combination with state-of-the-art multi-color reporter mice to assess Lgr5 stem cell function during epithelial renewal.

2) Intra-tumor lineage tracing from candidate Lgr5 cancer stem cell populations in mouse gastric cancer and ovarian cancer models.

3) Targeted mutation of Lgr5 stem cells in the stomach and ovary using the Lgr5-EGFP-ires-CreERT2 mice in combination with conditional mouse lines to assess the tumor-initiating potential of the Lgr5 stem cells.

4) Gene expression profiling of Lgr5 stem cell populations to reveal novel stem cell markers.

5) Conditional knockdown of Lgr5 on adult stem cells and their cancer counterparts to assess Lgr5 function in-vivo.

6) Develop human organoid culture systems for both basic research and potential therapeutic applications.

Group Members

Research Scientist Marc Leushacke
Senior Research Fellow Ryo Seishima
Research Fellows Aliya Fatehullah
  Tan Si Hui
  Carly Leung
Senior Research Officer Swathi Yada
Research Officers Tan Liang Thing

Jasmine Goh
  Sagiraju Sowmya
  Mohammad Amin Hajamohideen
Laboratory Officer Katzrin Murad

Leushacke M, Tan SH, Wong A, Swathi Y, Hajamohideen A, Tan LT, Goh J, Wong E, Denil SLIJ, Murakami K, Barker N. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol. 2017 Jun 5. doi: 10.1038/ncb3541. Link
Flanagan DJ, Barker N, Nowell C, Clevers H, Ernst M, Phesse TJ, Vincan E. Loss of the Wnt receptor frizzled 7 in the mouse gastric epithelium is deleterious and triggers rapid repopulation in vivo. Dis Model Mech. 2017 Aug 1;10(8):971-980. doi: 10.1242/dmm.029876 Link
Leushacke M, Barker N, Pin C. Quantifying Lgr5-positive stem cell behaviour in the pyloric epithelium. Sci Rep. 2016 Feb 26;6:21923. doi: 10.1038/srep21923 Link
Cammareri P, Rose AM, Vincent DF, Wang J, Nagano A, Libertini S, Ridgway RA, Athineos D, Coates PJ, McHugh A, Pourreyron C, Dayal JH, Larsson J, Weidlich S, Spender LC, Sapkota GP, Purdie KJ, Proby CM, Harwood CA, Leigh IM, Clevers H, Barker N, Karlsson S, Pritchard C, Marais R, Chelala C, South AP, Sansom OJ, Inman GJ. Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Nat Commun. 2016 Aug 25;7:12493. doi: 10.1038/ncomms12493. Link
Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol. 2016 Mar;18(3):246-54. doi: 10.1038/ncb3312. Link
Flanagan DJ, Phesse TJ, Barker N, Schwab RH, Amin N, Malaterre J, Stange DE, Nowell CJ, Currie SA, Saw JT, Beuchert E, Ramsay RG, Sansom OJ, Ernst M, Clevers H, Vincan E. “Frizzled7 functions as a Wnt receptor in intestinal epithelial Lgr5+ stem cells.” Stem Cell Reports. 2015 May 12;4(5):759-67. doi: 10.1016/j.stemcr.2015.03.003.
Goh AM, Xue Y1, Leushacke M, Li L, Wong JS, Chiam PC, Rahmat SA, Mann MB, Mann KM, Barker N, Lozano G, Terzian T, Lane DP. “Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice.” Oncotarget. 2015 Jul 20;6(20):17968-80
Horvay K, Jardé T, Casagranda F, Perreau VM, Haigh K, Nefzger CM, Akhtar R, Gridley T, Berx G, Haigh JJ, Barker N, Polo JM, Hime GR, Abud HE. “Snai1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium.” EMBO J. 2015 May 12;34(10):1319-35. doi: 10.15252/embj.201490881.
Huels DJ, Ridgway RA, Radulescu S, Leushacke M, Campbell AD, Biswas S, Leedham S, Serra S, Chetty R, Moreaux G, Parry L, Matthews J, Song F, Hedley A, Kalna G, Ceteci F, Reed KR, Meniel VS, Maguire A, Doyle B, Söderberg O, Barker N, Watson A, Larue L, Clarke AR, Sansom OJ. “E-cadherin can limit the transforming properties of activating β-catenin mutations.” EMBO J. 2015 Aug 3. pii: e201591739.
Ng A, & Barker N. “Ovary and fimbrial stem cells: biology, niche and cancer origins.” Nat Rev Mol Cell Biol. 2015 Sep 9. doi: 10.1038/nrm4056.
Ng A, Tan S, Singh G, Rizk P, Swathi Y, Tan TZ, Huang RY, Leushacke M, Barker N. Lgr5 marks stem/progenitor cells in ovary and tubal epithelia. Nat Cell Biol. 2014 Aug;16(8):745-57. doi: 10.1038/ncb3000. Epub 2014 Jul 6. PubMed PMID: 24997521. Link
Liu D, He XC, Qian P, Barker N, Trainor PA, Clevers H, Liu H, Li L. Leucine-rich repeat-containing G-protein-coupled Receptor 5 marks short-term hematopoietic stem and progenitor cells during mouse embryonic development. J Biol Chem. 2014 Aug 22;289(34):23809-16. doi: 10.1074/jbc.M114.568170. Epub 2014 Jun 25. PubMed PMID: 24966324; PubMed Central PMCID: PMC4156055. Link
Leushacke M, Barker N. Ex vivo culture of the intestinal epithelium: strategies and applications. Gut. 2014 Aug;63(8):1345-54. doi: 10.1136/gutjnl-2014-307204. Epub 2014 May 19. Review. PubMed PMID: 24841573. Link
Tan S, Barker N. Epithelial stem cells and intestinal cancer. Semin Cancer Biol. 2014 Feb 19. pii: S1044-579X(14)00029-7. doi: 10.1016/j.semcancer.2014.02.005. [Epub ahead of print] Review. PubMed PMID: 24560652. Link
Sun X, Terakawa J, Clevers H, Barker N, Daikoku T, Dey SK. Ovarian LGR5 is critical for successful pregnancy. FASEB J. 2014 May;28(5):2380-9. doi: 10.1096/fj.13-248344. Epub 2014 Jan 27. PubMed PMID: 24469993; PubMed Central PMCID: PMC3986831. Link
Tan DW, Barker N. Intestinal stem cells and their defining niche. Curr Top Dev Biol. 2014;107:77-107. doi: 10.1016/B978-0-12-416022-4.00003-2. Review. PubMed PMID: 24439803. Link
Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol. 2014 Jan;15(1):19-33. doi: 10.1038/nrm3721. Epub 2013 Dec 11. Review. PubMed PMID: 24326621. Link
Hirsch D, Barker N, McNeil N, Hu Y, Camps J, McKinnon K, Clevers H, Ried T, Gaiser T. LGR5 positivity defines stem-like cells in colorectal cancer. Carcinogenesis. 2014 Apr;35(4):849-58. doi: 10.1093/carcin/bgt377. Epub 2013 Nov 26. PubMed PMID: 24282287; PubMed Central PMCID: PMC3977143. Link
Leushacke M, Ng A, Galle J, Loeffler M, Barker N. Lgr5(+) gastric stem cells divide symmetrically to effect epithelial homeostasis in the pylorus. Cell Rep. 2013 Oct 31;5(2):349-56. doi: 10.1016/j.celrep.2013.09.025. PubMed PMID: 24209744. Link
Barker N, Tan S, Clevers H. Lgr proteins in epithelial stem cell biology. Development. 2013 Jun;140(12):2484-94. doi: 10.1242/dev.083113. Review. PubMed PMID: 23715542. Link
Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Heijmans J, Huels DJ, Moreaux G, Rupec RA, Gerhard M, Schmid R, Barker N, Clevers H, Lang R, Neumann J, Kirchner T, Taketo MM, van den Brink GR, Sansom OJ, Arkan MC, Greten FR. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013 Jan 17;152(1-2):25-38. doi: 10.1016/j.cell.2012.12.012. Epub 2012 Dec 27. PubMed PMID: 23273993. Link
Barker N, Oudernaarden A, Clevers H (2012). Identifying the Stem Cell of the Intestinal Crypt: Strategies and Pitfalls. Cell Stem Cell. 11:452
Leushacke M. and Barker N (2012). Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer. Oncogene, 31, 3009
Barker N, de Lau W, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es J, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H (2011). Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature, 476:293
Barker, N., Bartfeld, S., and Clevers, H (2010). Tissue-Resident Adult Stem Cell Populations of Rapidly Self-Renewing Organs. Cell Stem Cell, 7:656
Barker N, Huch, M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom, R and Clevers H (2010). Lgr5+ve Stem Cells Drive Self-Renewal in the Pyloric Stomach and Build Long-Lived Pyloric Gastric Units In-Vitro. Cell Stem Cell 6:25
Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, and Clevers H. (2009). Crypt stem cells as the Cells-of-Origin of Intestinal Cancer. Nature, 457:608
Sato T, Vries R, Snippert H, van de Wetering M, Barker N, van Es JH, Abo A, Kujala P, Peters PJ, and Clevers H. (2008). Single intestinal stem cells build crypt-villus structures in vitro in the absence of a cellular niche. Nature, 459:262
Barker N, Jaks V, Kasper M, van Es JH, Clevers H, Snippert, HJ and Toftgard R. (2008) Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature Genetics 40:1291
Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003.
Barker, N, Hurlstone, H, Musisi, H, Miles, AH, Bienz, M., & Clevers, H. (2001) The SWI/SNF component Brg-1 interacts with b-catenin to promote transcriptional activation. EMBO J. 20:4935.
Korinek, V, Barker, N, Moerer, P, van Donselaar, E, Huls, G, Peters, P, and Clevers, H. (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genetics 19: 279.
Barker, N, Korinek, V, Morin, P, van Wichen, D, de Weger, R, Kinzler, KW, Vogelstein, B, and Clevers, H. (1997) Constitutive transcriptional activation by a b-catenin-Tcf complex in APC-/- colon carcinoma. Science 275:1784.