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Postgenome Technology Illuminates Cancer Biology at Eighth Armenise Symposium
For nearly 500 years, robed monks lived contemplative lives at the Certosa di Pontignano, a complex of chapels and cloisters sequestered in the olive groves and vineyards outside Siena, Italy. Removed from the crowding, political infighting, and epidemic disease that roiled Tuscany's second city, members of the Carthusian Order devoted themselves to scholarship and meditation from the 1340s until the late 18th century. Today, the Certosa is a retreat of a different kind--a jewel-like conference center belonging to the University of Siena.
David Altshuler, HMS associate professor of genetics and of medicine at Massachusetts General Hospital, explains his work to Raju Kucherlapati, the Paul C. Cabot professor of genetics at HMS, at the eighth annual symposisum of the Giovanni Armenise-Harvard Foundation in Certosa, Italy.
For three days in late May, 80 researchers from HMS and 11 Italian institutions converged on the Certosa for the eighth annual symposium of the Giovanni Armenise-Harvard Foundation. During breaks between sessions, molecular biologists used high-speed Internet connections in rooms where monks once pored over illuminated manuscripts.
The symposium marks the second time the foundation has devoted its flagship conference to the rapidly shifting landscape of "Cancer Biology, Genomics, and Post-Genomics," said co-organizer Peter Howley, the Shattuck professor of pathological anatomy and chairman of the HMS Department of Pathology. "Using our meeting of three years ago as a benchmark, clearly there have been significant advances," Howley said. He and co-organizer Philip Leder, the John Emory Andrus professor of genetics and head of the HMS Department of Genetics, invited 20 speakers whose work illustrates a spectrum of new technologies and ways of thinking about cancer biology.
Downside of Longevity
The symposium's keynote speaker, Pier Giuseppe Pelicci, is widely known for uncovering key elements in what Howley characterized as "the yin and yang of extended life span," the idea that an increased risk for cancer may be the price for expressing genes associated with longevity. Contrary to a forecast that Pelicci said he once made, experiments in his lab at the Milan-based European Institute of Oncology showed that deleting p66shc, an oxidative stress regulator, extended the life span of mice without raising tumor risk. This provocative finding has stimulated a flurry of work in Pelicci's lab and many others, and Howley anticipates this will become an even hotter topic as people live longer and worry that cancer might be inevitable.Other presentations with tantalizing clinical possibilities focused on expression signatures that might help determine the prognosis for cancer patients or how responsive their tumors will be to different drugs. "Expression signatures are going to have significance and meaning," said Leder, who cited the work of University of Torino researcher Enzo Medico as a case in point. Medico applied two commercially available microarray platforms to samples taken from murine liver cancers and identified a set of genes correlated with invasive growth. By comparing these results with published microarray data from human breast cancers, he identified 20 genes that define a subgroup of patients with an 85 percent chance of metastasis within 2.5 years.
Antonio Sica of the University of Milan also used cDNA and RNA chips to capture the entire "transcriptome" of breast cancer samples. This genomewide analysis showed that when macrophages flood the oxygen-poor interior of tumors, recruit more of their own, and then promote both cell survival and new blood vessel growth, the outlook for the patient worsens.
Fly Screens
Microarrays were not the only powerful postgenome technology that had its moment under the Tuscan sun. Howard Hughes investigator and HMS geneticist Norbert Perrimon's description of the Drosophila RNAi Screening Center (DRSC), for example, excited considerable interest among Italian investigators. Perrimon explained how the DRSC's highly automated system can be used to determine the genomewide impact of eliminating a single protein. He emphasized that these screens can be performed--quickly and at a reasonable cost--for researchers anywhere in the world.On another front, Cynthia Morton, the William Lambert Richardson professor of obstetrics, gynecology and reproductive biology at HMS, described two projects that are accelerating the search for genes implicated in congenital abnormalities and cancer. Both use fluorescent in situ hybridization (FISH) to localize chromosomal breakpoints, which are then cloned and analyzed with microarrays for gene expression or screened for function against the annotated genomes of model organisms, said Morton, also an HMS professor of pathology at Brigham and Women's Hospital. The Developmental Genome Anatomy Project has already identified gene disruptions in a complex seizure phenotype, and the Tumor Genome Anatomy Project has found a deletion that correlates with a poor prognosis for a subgroup of leukemia patients. Morton expects many more revelations to follow.
At the close of the symposium, Howley marveled at how swiftly some technologies, such as RNA interference and sensitive mass spectroscopy, have gone from being exotic to routine. Even more exciting is the certainty that new tools are being developed all the time. "Dr. Leder and I look forward to joining our colleagues in Italy in organizing a meeting with a similar theme in three years, and we expect further advances both in the technology and in our understanding of cancer," Howley said.
--Patricia Thomas