PEDIATRIC SARCOMA, RHABDOMYOSARCOMA, AND MECHANISMS OF ORIGIN:
My lab?s research efforts are based upon a fundamental interest in the genetic and molecular mechanisms involved in childhood cancer. Within the group of malignant tumors that afflict children, those that grow from the skeleton and soft tissues (for example, muscle, fat) are called sarcomas and are particularly aggressive. Little is understood about how these cancers arise, explaining in part why they have been so clinically difficult to treat and cure. To attempt to address these issues, I study one of the most aggressive of these soft-tissue cancers, the skeletal muscle-type tumor called alveolar rhabdomyosarcoma (ARMS).
The critical genetic abnormality responsible for the development of ARMS causes two otherwise normal genes, named PAX and Forkhead in Rhabdomyosarcoma (or FKHR), to be abnormally fused together into one gene, called PAX-FKHR. This abnormal fusion gene is cancer-inducing, converting originally normal tissue into malignant cancer cells. Little is known, however, regarding how PAX-FKHR changes normal cells to cancer cells.
To answer crucial questions in ARMS biology, I have undertaken a new approach by utilizing one of the powerful research organisms available to scientific geneticists, the fruit fly Drosophila melanogaster. My rationale for utilizing the fruit fly includes: 1) Decades of experimental work (rewarded with the Nobel Prize in Physiology or Medicine in 1995) have shown that, for virtually every important human gene, including cancer-related genes, a similar gene exists in the fruit fly; & 2) While having similar physiology, the fruit fly is biologically ?more-simple? than humans, allowing for easier experimental manipulation, observation, and interpretation. Because of these benefits, I have been able to genetically engineer the fruit fly to express the actual human PAX-FKHR gene. Since the fly possesses similar PAX and FKHR genes in its DNA, the fly recognizes and responds to PAX-FKHR in ways similar to human cells. With this new strain of PAX-FKHR flies, which due to the comparatively small size of the animal can be entirely examined while alive under the microscope, I am now actively profiling in living animals how PAX-FKHR changes cell biology.
Additionally, no individual gene, whether normal or mutant, ever functions completely alone. Instead, co-factors always participate in all cellular processes. Using techniques that are only available when experimenting with model animals like the fruit fly, my lab is systematically manipulating virtually every individual gene in the fly?s DNA (?unbiased forwarded genetic screening) to identify previously unrecognized co-factors that function in concert with PAX-FKHR to convert cells to cancer. This approach is proving quite successful and is allowing for our identification of these participant genes. Importantly, the identity of these genes, and knowing from previous studies in other cellular processes how these genes often function, helps to explain how PAX-FKHR damages skeletal muscle.
By uncovering how PAX-FKHR cells undergo cancer transformation and isolating the previously unknown genes involved in this process, we hope to provide avenues for new therapeutic drugs, as well as the refinement of other ARMS experimental systems, which should significantly improve our future ability to treat these deadly tumors.
RESEARCH INTERESTS
Pediatric Tumor Biology
Rhabdomyosarcoma
PAX/FKHR/FOXO1A Cell Signaling
Muscle Biology, Development, Maintenance, and Disease
Model Organisms of Human Biology and Disease
RECENT PUBLICATIONS
Galindo RL, Allport J, and Olson EN., "A Drosophila model of the Rhabdomyosarcoma Initiator PAX7-FKHR." Proc Natl Acad Sci USA., 103:13439-13444., 2006
Verret DJ, Galindo RL, DeFatta RJ, and Bauer PW., "Sialoblastoma: a rare submandibular gland neoplasm." Ear Nose Throat J., 85:440-442, 2006
Rakjeha D, Cimo ML, Ramus RM, Rogers BB, Bennett MJ, Boyer PJ, and Galindo RL., "Hydrolethalus syndrome, in contrast to Smith-Lemli-Opitz syndrome, is not due to a defect in post-squalene cholesterol biosynthesis: a case report." Am J Med Genet., 129A:212-213, 2004
Steinberg JP, Galindo RL, and Kraus ES., "Disseminated acanthamebiasis in a renal transplant recipient with osteomyelitis and cutaneous lesions: case report and literature review." Clin Infect Dis., 35:E43-49, 2002
SIGNIFICANT PUBLICATIONS
Galindo RL, Allport J, and Olson EN., "A Drosophila model of the Rhabdomyosarcoma Initiator PAX7-FKHR." Proc Natl Acad Sci USA., 103:13493-13444, 2006
Liu ZP, Galindo RL, and Wasserman SA., "A role for CKII phosphorylation in dorsoventral patterning of the Drosophila embryo." Genes Dev., 11:3413-3422, 1997
Reach M*, Galindo RL*, Towb P, Allen JL, Karin M, and Wasserman SA., "A gradient of Cactus protein degradation establishes dorsoventral polarity in the Drosophila embryo." Dev. Biol., 180:353-364, 1996
Galindo RL, Edwards DN, Gillespie SKH, and Wasserman SA., "Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos." Development, 121:2209-2218, 1995
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