Cancer is a fundamentally genetic disease and several CSHL scientists are involved in systematic efforts to detect cancer-linked mutations.  Michael Wigler and Robert Lucito developed ROMA (Representational Oligonucleotide Microarray Analysis), one of the most sensitive, comprehensive, and robust techniques that currently exist for profiling c opy number polymorphisms in human cancers.  Mike Wigler, Rob Lucito, Scott Powers and others have used this technique to identify deletions and amplifications in breast cancer, ovarian and pancreatic tumors and leukemia and lymphoma.  The aim of this research is to obtain a complete profile of the molecular and physiological abnormalities that underlie all major forms of human cancer.  Ultimately, the goal is to use this information to develop improved diagnostic and therapeutic measures.  

Bioinformatics
Scientists are increasingly faced with the task of organizing and interpreting vast amounts of genome research data.  Bioinformatics faculty at CSHL study a broad range of topics in close collaboration with our "wet lab" scientists.  For example, Lincoln Stein has developed several powerful databases, including an extraordinarily useful tool called Reactome, a curated, hierarchically organized, internally cross-referencing database of all known  biological processes in humans.   Michael Zhang is developing methods for detecting key genetic elements within the complex landscape of the human genome sequence. And finally, computer scientists working with Mike Wigler have developed several sophisticated mathematical and computational methods for analyzing the results from ROMA, traditional DNA microarray, and other wet lab experiments.  

CSHL is a principal participant and software developer in the National Cancer Institute's Cancer Bioinformatics Group (caBIG).  caBIG is an ambitious project whose goal is to create a bioinformatics network for sharing data and computational resources among all of NCI's Cancer Centers.  

Mouse Models of Human Cancer
Cancer Center faculty including Scott Lowe, Alea Mills and Gregory Hannon have made extraordinary progress in using genetically well-defined mouse models to examine cancer-related processes, evaluate new therapies and explore strategies for overcoming drug resistance.  One extremely promising development in this area stems from a novel lymphoma model in which genetically defined tumors can readily be produced from fetal liver hematopoietic cells.  Using this model, Dr. Lowe has been able to rapidly generate tumors with defined genetics for cancer therapy research.

Alea Mills utilizes a technique of “chromosome engineering” to generate mouse models that can be used for cancer gene mapping and evaluation of cancer therapy regimens.  Using a Cre/loxP-based recombination strategy, she generated deletions on mouse chromosome 4, a region syntenic with human chromosome 1p that is implicated in many types of human cancer. Mouse strains carrying heterozygous deletions that displayed an increased risk for developing tumors were used to functionally identify tumor suppressor genes that are key in the tumorigenic process. These efforts led to the identification of a new tumor suppressor gene, CHD5.

Three Cancer Center faculty members (Drs. Lowe, Hannon, and Muthuswamy) have been awarded a grant from the NCI's Mouse Models of Human Cancer Consortium. Efforts are underway to develop and refine mouse models of human cancer as preclinical models to test new strategies for therapy and for overcoming drug resistance.  These studies will provide resources for the rapid in vivo evaluation of new candidate oncogenes and tumor suppressor genes as they are uncovered by cancer gene discovery methods. This work will involve measuring how patterns of gene activity change in response to treatment regimens in vivo, and will include the rational, targeted use of RNAi and other methods to sensitize otherwise resistant tumors to the effects of particular therapies. 

 Mammalian cell genetics
Greg Hannon’s lab has constructed libraries of short hairpin RNAs that can be used to silence specific genes in human or other mammalian cells.  These libraries cover approximately 32,000 open reading frames in the human genome, 32,000 in the mouse genome 27,000 in the rat genome.  Each gene is targeted by at least three independent shRNAs and all clones will be sequence verified in collaboration with Dick McCombie’s laboratory. The shRNA genes can readily be transferred by bacterial mating into many vectors, including lentivirus, retrovirus and selectable plasmids. The libraries provide molecular tools in experiments to understand the functions of human cancer genes identified in gene discovery efforts and to screen for synthetic lethality in cancer cells to discover new cancer therapeutic targets.

Tissue Biology
The cells in tissue live in a complex three-dimensional organization and information from biochemical signals direct them to live or die, to grow or stop growing, or to migrate or stop migrating.  One hallmark of cancer is that cells lose their ability to detect or respond properly to such signals.  Invasion and metastasis are particularly insidious because when tumors remain in situ, cancer therapies are frequently far more successful.   We believe that methods for culturing cells in 3-D and other tissue biology approaches fill an important niche between traditional 2-D cell cultures and whole animal models.   Senthil Muthuswamy utilizes 3-D cultures of human and mouse breast epithelium to explore the critical first steps in invasive breast cancer. Like the majority of other solid tumor types, breast tumors arise from epithelial cells, thus Dr. Muthuswamy's findings may impact the diagnosis and treatment of many different cancer types. In addition, Dr. Vivek Mittal studies mechanisms of tissue angiogenesis, again emphasiz ing a move toward cancer tissue biology.

Increased Emphasis on Translational Cancer Research
CSHL has long been involved with integrating basic and clinical research and has a well-established network of clinical collaborations in place.  The CSHL Cancer Center is working to expand and strengthen its translational cancer research efforts and to significantly increase the proportion of the resources it allocates to translational research. 
A crucial element of translational research at CSHL will be the continued formation and expansion of its collaborations on using ROMA for cancer diagnosis and prognosis with clinicians from a number of institutions including MSKCC, Johns Hopkins School of Medicine, Columbia University Medical School, NYU Medical School, Stony Brook University Medical School,
the Karolinska Institute in Sweden and the Norwegian Radium Hospital.

Basic Research
CSHL has a strong program in basic research to understand the basic biochemical, molecular and cellular biology processes necessary for cell function.  These efforts are an essential component of the CSHL Cancer Center.  Basic research supports and strengthens the programs in drug discovery and animal models by clarifying the pathways and mechanisms in normal versus cancer cells and providing an understanding of the mechanism of action of cancer drugs.  Basic research can also lead to discovery of new cancer genes.  For example, Adrian Krainer, in studies of the biochemistry of mRNA splicing, found that the RNA splicing factor SF2/ASF can act as a cancer-causing protein by changing the alternative splicing of other genes critical for growth-control of cells.

Reactome
caBIG
model
libraries of short hairpin RNAs
SF2/ASF