Widely known for its pioneering work in developing the techniques that permit gene targeting in the mouse, the Capecchi Laboratory develops and studies mouse models of many human disorders and diseases. The laboratory has a specific interest in the genetics of sarcomas. Genetically, sarcomas can be divided into two groups, those with single, specific gene alterations, called balanced chromosomal translocations, and those with multiple and variable gene alterations and mutations.
Specific, balanced chromosomal translocations result in the creation of unique combination genes, called fusion genes. A fusion gene will include the beginning of one gene and the end of a second, otherwise separate gene. A fusion gene thus gains functions that neither of its contributing genes had prior to the translocation. Certain fusion genes are associated with specific subtypes of sarcoma, such as Ewing sarcoma, synovial sarcoma, alveolar rhabdomyosarcoma, and others. The creation of one of these type-specific fusion genes by chromosomal translocation is suspected to be the initiating event for these cancers. In the Capecchi Laboratory, this theory is tested for each tumor type by engineering the specific sarcoma-associated fusion genes into the mouse genome. Not only are these experiments proving in many cases that fusion genes can indeed initiate sarcoma formation, but they also are providing excellent mouse models of these cancers for pre-clinical testing of chemotherapies and other treatment methods.
The second group of sarcomas, those with complex genetic alterations and mutations, is also studied by the Capecchi Laboratory. The model disease for these investigations is osteosarcoma. Unlike most genetically complex cancers, such as breast, prostate, or lung carcinomas, osteosarcoma typically arises in young people. This fact argues that osteosarcoma is initiated by a single or a few genetic alterations that then result in an unstable genome and yield the many and varied genetic alterations that are present by the time a patient notices the cancer. Sorting out the early and initiating events has proven very difficult for osteosarcoma. In the Capecchi Laboratory, genetic information from osteosarcoma patients and their tumors is applied to generate mice with specific gene alterations as well as combinations of gene alterations to test their effects on the formation and progression of osteosarcoma.
Currently, four scientists in the laboratory focus the majority of their efforts on sarcoma genetics, Malay Haldar, Ben Illum, Kevin Jones, and Emanuele Panza. Overall, the goal of the laboratory in relation to sarcoma is to improve understanding of the biology at work in these rare cancers. Increased understanding of their tumor biology can reveal the vulnerabilities of different types of sarcomas and therefore avenues toward more effective treatments.