Uniformed Services University of the Health Sciences
Department of Pathology
4301 Jones Bridge Road, C1094
Bethesda, Maryland 20814-4799
Phone: (301) 295-3450
Fax: (301) 295-1640
Director of Molecular and Cell Biology Graduate Education Program
Associate Director for Basic and Translational Science, United States Military Cancer Institute
My research focuses on the contributions of the transforming growth factors, oncogenes and tumor suppressor genes to the malignant transformation of cells and the loss of differentiated cell functions. Ongoing projects include the study of Rsu-1, the Ras suppressor molecule, the mechanisms by which it regulates tumor cell adhesion and the role of adhesion in the response of tumor cells to chemotherapeutic agents. The other area of research in my lab focuses on the control of mammary epithelial cell differentiation during development.
Rsu1 was identified based on its property of specifically suppressing Ras transformation in both fibroblasts and epithelial cells. The defining elements of the Rsu-1 protein are a series of amphipathic leucine-based repeats, referred to as leucine-rich repeats or LRR which bind to the adaptor protein PINCH1 (Dougherty et al. 2005, 2008). A complex of parvin-integrin linked kinase (ILK)-PINCH1-Rsu-1 participates in cell adhesion by linking beta subunits of integrin to the actin cytoskeleton. The knockdown of any of these proteins in cell culture results in loss of cell adhesion.
Ectopic Rsu-1 expression prevents both oncogenic growth of specific human glial and breast tumor cell lines and tumor formation in a nude mouse model. Screening human tumors for RSU-1 loss and mutation revealed that glial tumors frequently expressed an altered spliced product of the RSU-1 gene. This RNA is missing a single exon and encodes an Rsu-1 protein lacking the COOH terminus (Chunduru et al. 2002). Alternative splicing of Rsu-1 in human tumor cell lines is dependent on activation of Ras pathway (Dougherty et al., 2008) and studies examining the regulatory function of the alternatively spliced RNA in breast and glial tumors are ongoing in the lab.
The impact of tumor cell adhesion on the response of solid tumors to chemotherapy is an application of our work on the parvin-ILK-PINCH1-Rsu-1 complex and we are pursuing this project in collaboration with Dr. Peter D’Arpa, an expert on topoisomerase function.
Epidemiological evidence indicates that early pregnancy and lactogenic differentiation can reduce the risk of both pre- and post-menopausal breast carcinoma. Hence, a complete understanding of the regulation of mammary differentiation is important in elucidating the mechanisms leading to breast carcinogenesis. Global expression profiling of mammary epithelial cells undergoing lactogenic differentiation identified the matricellular protein connective tissue growth factor (CTGF/CCN2) as highly up regulated during lactogenic differentiation and that CTGF/CCN2 binding to ?1 integrin is required for differentiation (Wang et al. 2007 and Morrison et al. 2010). The potential application of this work to human breast cancer is significant because the molecular signature of genes transcriptionally activated during differentiation includes a number of transcripts that are found at high levels in breast tumors that metastasize to bone, a site of CTGF/CCN2 expression. Hence, the results of our analysis of differentiating mammary epithelial cells may help define elements of transcriptional control that are important for tumor progression in this tissue.
Chunduru S, Kawami H, Gullick R, Dougherty G and Cutler ML. Identification of an alternatively spliced form of the Ras Suppressor RSU-1 in human gliomas. Journal of Neuro-Oncology 60: 201-211. 2002.
Cerritto MG, Galbaugh T, Chopp T, Wang W, Salomon D and Cutler ML. Dominant negative Ras enhances lactogenic hormone-induced differentiation by blocking activation of the Raf-Mek-Erk signal transduction pathway. Journal of Cellular Physiology, 201:244-258, 2004.
Dougherty G, Chopp T, Qi SM and Cutler ML. The Ras suppressor Rsu-1 binds to the LIM5 domain of the adaptor protein PINCH1 and participates in adhesion-related functions. Experimental Cell Research, 306: 168-179, 2005.
Galbaugh T, Cerrito MG, Jose C, Cutler ML. EGF-induced activation of Akt results in mTOR-dependent p70S6 kinase phosphorylation and inhibition of HC11 cell lactogenic differentiation. BMC Cell Biology, 7:34, 2006.
Gao CF, Furge K, Koeman J, Dykema K, Su Y, Cutler ML, Werts A, Haak, P, and Vande Woude GF. Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proc. Nat. Acad. Sci. 104:8995-9000, 2007.
Dougherty G, Jose C, Gimona M and Cutler ML. The Rsu-1- PINCH1-ILK complex is regulated by Ras activation in tumor cells. European Journal of Cell Biology, 87:721-734, 2008.
Wang W, Jose C, Kenney N, Morrison B and Cutler ML. Global expression profiling reveals transcriptional regulation of CTGF/CCN2 during lactogenic differentiation. Journal of Cell Communication and Signaling, 3:43-55. 2009.
Morrison B, Kenney N, Jose C, and Cutler ML. Connective Tissue Growth Factor/CCN2 enhances lactogenic differentiation of mammary epithelial cells via integrin-mediated cell adhesion. BMC Cell Biology 11:35. 2010.
Morrison B and ML Cutler. The contribution of adhesion signaling to lactogenesis. Journal of Cell Communication and Signaling. 4:131-139. 2010.
Morrison B and ML Cutler. The Contribution of CTGF/CCN2 and adhesion signaling to lactogenesis. In Dietary and Nutritional Aspects of Human Breast Milk. Academic Publishers, Wageningen, the Netherlands. 2012.