Scientists identify a novel mechanism for evolution of highly aggressive cancers

Dr Frank McKeon, Senior Group Leader of the Stem Cell and Developmental Biology at A*STAR's Genome Institute of Singapore (GIS), and Principal Investigator Dr Wa Xian at A*STAR's Institute of Medical Biology (IMB), together with their counterparts from the Harvard Medical School, the Brigham and Women's Hospital in Boston, and the National University of Singapore, have made the striking finding that Barrett's esophagus[1] work, published online in the journal Cell on 24 June 2011, is essential to developing therapeutics for esophageal cancer., the precursor of the most deadly esophageal cancer[2], can form without mutations in a matter of a few days. The

The scientists discovered that Barrett's esophagus arises from a very small group of embryonic cells that exist in all adults at the junction of the esophagus and the stomach. In most people, these embryonic cells are restricted to that junction. However, if the esophagus becomes damaged by acid reflux, these embryonic cells rapidly grow to exploit this opportunity and form the unusual, intestine-like tissue of Barrett's esophagus.

Using an independent mouse model to test the origins of Barrett's metaplasia[3] in adult animals, the scientists examined the molecular properties and evolution of metaplasia in mice, as a means to speeding up the development of esophageal cancer therapies in human. As treatment for late stage esophageal cancer is challenging and largely palliative, a better knowledge of the earlier, precancerous stage of this disease, such as Barrett's esophagus, serves as a prerequisite to developing therapeutic approaches.

Dr Wa, corresponding author of the publication in Cell, noted that "the exciting feature of this work is that these embryonic cells are present in everyone and do not have to be mutated to become a major threat as a high-risk cancer precursor cell. Preliminary work in the lab suggests our findings in Barrett's esophagus provide a valid model to explain a subset of particularly aggressive cancers for which modern medicine does not have therapeutic options".

Another author of the work, Dr Ho Khek Yu, an endoscopic surgeon specializing in Barrett's esophagus and Head of the Department of Medicine at National University of Singapore, added "Recent efforts to prevent the formation of esophageal cancer by removing the cells forming Barrett's esophagus before they turn cancerous have met with considerable setbacks. The study suggests a new way to prevent esophageal cancers: target these embryonic cells before they can form Barrett's esophagus. If the method is successful, we will have eradicated one major risk factor of esophageal cancer."

Corresponding author Dr Frank McKeon of the GIS and Harvard Medical School said, "we now have a great deal of information about these unusual embryonic cells that give rise to Barrett's esophagus and are working with clinicians to develop novel monoclonal antibodies to eliminate these cells before they become malignant. This type of preventive therapy directed at the precursors of these cancers is the rational approach to stamping out the disease, which has risen five-fold in the last 30 years."

Dr Yusuke Yamamoto, a senior postdoctoral fellow at the GIS, expert in bioinformatics and stem cell biology, and co-first author of the publication, noted, "I am continually amazed by the speed with which mouse genetic models, bioinformatics, and stem cell biology come together in Singapore to provide such a vivid image of disease processes and identify genes that represent the most important prevention and therapeutic targets".

Profs Barbara Knowles and Davor Solter, Senior Principal Investigators of the Mammalian Development Laboratory at the Institute of Medical Biology in Singapore commented, "An excellent piece of scientific sleuthing with a tantalizing approach to cancer prevention".

Prof Lee Eng Hin, Executive Director of A*STAR's Biomedical Research Council, said, "The work is an excellent example of clinicians, bioinformaticians, stem cell biologists, and geneticists coming together in Singapore to understand disease processes. Cross-disciplinary collaborations between scientists and clinicians such as this will go far in establishing Singapore as Asia's Innovation Capital and a global research hub."

Research publication: The research findings described in the press release can be found in the 24 June, 2011 advance online issue of Cell under the title "Residual Embryonic Cells as Precursors of a Barrett's-Like Metaplasia".

Authors:
Xia Wang1,9, Hong Ouyang1,9, Yusuke Yamamoto2,9, Pooja Ashok Kumar2,
Tay Seok Wei3, Rania Dagner4, Matthew Vincent5, Xin Lu6,
Andrew M. Bellizzi7, Ho Khek Yu8,
Christopher P. Crum7, Wa Xian3,7* and Frank McKeon1,2*

1 Dept. Cell Biology, Harvard Medical School, Boston, MA USA;
2 Genome Institute ofSingapore and
3 Institute of Medical Biology, A-STAR, Singapore;
4 Institut de Science et d'Ingénierie Supramoléculaires, University of Strasbourg, Strasbourg, France;
5 Multiclonal Therapeutics, Inc., Boston, MA, USA;
6 Ludwig Cancer Institute, Oxford University, UK;
7 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA;
8 Department of Medicine, Yong Loo Lin School of Medicine, National University ofSingapore, Singapore.

9 These authors contributed equally to this work

*Please address all correspondence to the following:

Wa Xian, Ph.D.
Institute of Medical Biology
8A Biomedical Grove
6-06 Immunos
Singapore 138648
65-9751-3768

and

Frank McKeon, Ph.D.
Genome Institute of Singapore
60 Biopolis Street, #02-01,
Singapore 138672
65-9751-3768

The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine. The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.

For more information about GIS, please visit www.gis.a-star.edu.sg

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia & centres, located in Biopolis and Fusionopolis as well as their immediate vicinity.

A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.

For more information about A*STAR, please visit www.a-star.edu.sg.

For more information, please contact:

Winnie Serah Lim (Ms)
Genome Institute of Singapore
Corporate Communications
Tel: (65) 6808 8013
Email: limcp2@gis.a-star.edu.sg

Prudence Yeo (Ms)
Corporate Communications
Genome Institute of Singapore
Corporate Communications
Tel: (65) 6808 8010
Email: yeojp@gis.a-star.edu.sg

[1] A disorder in which the lining of the esophagus (the tube that carries food from the throat to the stomach) is damaged by stomach acid.
[2]Esophagal cancer is lethal in most cases and significantly decreases the quality of life. (http://emedicine.medscape.com/article/277930-overview)
[3] Transformation of cells from a normal to an abnormal state.