Selected publications

• Bodmer Walter and Bonilla Carolina (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet, 40(6):695-701.

• Chan Carol WM, Wong Newton A, Liu Ying, Bicknell David, Turley Helen, Hollins Laura, Miller Crispin J, Wilding Jennifer L, and Bodmer Walter F (2009) Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1. Proc Natl Acad Sci U S A, 106(6):1936-41.

• Ashraf S Q, Umana P, Mossner E, Ntouroupi T, Brunker P, Schmidt C, Wilding J L, Mortensen N J, and Bodmer W F (2009) Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis. Br J Cancer, 101(10):1758-68.

• Yeung Trevor M, Gandhi Shaan C, Wilding Jennifer L, Muschel Ruth, and Bodmer Walter F (2010) Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A, 107(8):3722-7.

• Yeung Trevor M, Gandhi Shaan C, and Bodmer Walter F (2011) Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci U S A, 108(11):4382-7.

Sir Walter Bodmer

The major interests of this laboratory are in:

i) The fundamental genetics and biology of colorectal cancer (CRC) and their potential applications; and

ii) The characterisation and population distribution of genetic diversity in human populations, especially of the British Isles.

We have accumulated a panel of more than 100 colorectal carcinoma derived cell lines, representing more than 90 different independent tumours. The lines are extensively characterised with respect to genetic and epigenetic changes, as well as whole genome mRNA expression and other biological properties. The lines thus provide an invaluable resource for studying the basic biology of CRC, as well as CRC drug responses in relation to tumour properties.

We have, for example, been able to identify cancer stem cells in the lines and shown the importance of the homeobox gene, CDX1, for the control of columnar cell differentiation, as well as the role of hypoxia in blocking differentiation. We are now extending our studies to the identification of the major genes that control stemness and cellular differentiation in CRCs.

We have shown that the response of the cell lines to the direct effects of the anti EGFR monoclonal antibody, cetuximab, is strongly associated with being triple KRAS, BRAF, PIK3CA wild type and highly expressing epiregulin, closely paralleling clinical data. The immune mediated effects (largely ADCC), however, correlate with ERBB1 levels and not with the KRAS mutation status, effects that can only be seen with a sufficiently large number of lines. We are now working on characterising the responses of the cell lines to a wide variety of different drugs and antibodies and their combinations, with a view to identifying new effective treatment combinations and so helping to optimize the clinical treatment of CRCs.

Recently, we have had considerable success in growing out medium to long-term cultures from fresh CRC tumour material. These primary cultures are now being compared with the cell lines, both with respect to their biological properties and their drug responses.

We have a major interest in the study of genetic variability in human populations and have collected a control UK population that can be used for case-control and rare variant disease association studies, as well as providing the basis for characterising the genetic variation of the British population in relation to its history and origins. We have now accumulated more than 4000 DNA samples from people from throughout the UK in rural areas, all four of whose grandparents come from the same area. This approach aims to minimise the effects of more recent population admixture. A novel approach to the analysis of 500k snp data on a subset of over 2000 samples, in collaboration with colleagues in the statistics department, has shown remarkable geographic patterning of the genetic variability in the UK. We are also studying the genetics of normal differences, especially of facial features, in these population samples (see the website: http://www.peopleofthebritishisles.org/).

A single CD44+CD24+ cell from the SW1222 colorectal cell line can give rise to a large colony containing multiple differentiated cell types when grown in 3D matrigel: AUA-1 (anti-EPCAM pan- epithelial marker), CDX1 (enterocyte), chromogranin (enteroendocrine), and PRD4 (mucin, goblet cell). Such colonies reproduce themselves and form tumours efficiently in immunocompromised mice. They thus have all the characteristics expected of cancer stem cells.