Professor and Chair
540 E. Canfield, 6374 Scott Hall
Office Phone(313) 577-1580
Office Fax(313) 577-6739
Cellular and Molecular Pharmacology:Signal Transduction through Small GTPases of the Ras Superfamily
Our studies focus on the physiological roles and pharmacological significance of small GTPases of the Ras superfamily. In particular, we are interested in how to target disorders where the Ras pathway is activated without direct oncogenic mutation of the Ras protein itself. While such activating changes in Ras are the most common oncogenic mutations in human cancer, the majority of cancers and many other hyperproliferative disorders have increased Ras signal transduction that is driven through other mechanisms. In recent years, our efforts have concentrated in the areas of Type 1 Neurofibromatosis (NF1) and breast cancer.
NF1 is the most frequent genetic cause of both tumors and neurological problems, with a birth incidence of about 1 in 3,000. Nearly all patients have benign neurofibromas, and there is increased risk of malignant peripheral nerve sheath tumors and other cancers. There is no effective current pharmacological treatment for these tumors. We have developed collaborative projects with the goal of the identification of non-toxic and mechanistically specific drugs for NF1 treatment. Our hypothesis is that increased activation of Ras signaling underlies the pathological development of NF1 and provides therapeutic targets.
Our work in breast cancer research is focused on the identification of new therapeutic approaches through the development and use of novel 3D in vitro models. We believe that this approach will provide more relevant results than are obtained from testing new drugs in conventional cell culture in 2D on plastic dishes, while being significantly more rapid and high-throughput than testing in animals. We are addressing two main problems: discovery of the factors that cause the progress from ductal carcinoma in situ (DCIS) to find how to block malignant progression; and identification of a viable targeted approach to triple-negative disease/basal-type breast cancer. We expect that the models and approaches that we are developing will address both of those challenges, and also be useful to other investigators who are tackling other important issues in breast cancer.
B.A. (Hons.), Natural Sciences/Pharmacology, University of Cambridge, Cambridge, U.K., 1987
Ph.D., Pharmacology, University of Virginia, Charlottesville, VA, 1993
- M. Sameni, S. Anbalagan, M.B. Olive, K. Moin, R.R. Mattingly & B.F. Sloane. MAME models for 4D live-cell imaging of tumor:microenvironment interactions that impact malignant progression. J. Vis. Exp. 60: e3661, DOI: 10.3791/3661, 2012.
- H. Kaur, S. Mao, Q. Li, M. Sameni, S.A. Krawetz, B.F. Sloane & R.R. Mattingly. RNA-seq of human breast ductal carcinoma in situ models reveals aldehyde dehydrogenase isoform 5A1 as a novel potential target. PLoS ONE 7(12): e50249. doi:10.1371/journal.pone.0050249 (2012)
- R.R. Mattingly. Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins. ISRN Oncol. Doi: 10.1155/2013/536529 (2013)
- A. Hammer, L. Rider, P. Oladimeji, L. Cook, Q. Li, R.R. Mattingly & M. Diakonova. Tyrosyl phosphorylated PAK1 regulates cell motility in response to prolactin through filamin A. Mol. Endocrinol. 27: 455-465 (2013)
- J.M. Rothberg, K.M. Bailey, J.W. Wojtkowiak, Y. Bennun, M. Bogyo, E. Weber, K. Moin, G. Blum, R.R. Mattingly, R.J. Gillies & B.F. Sloane. Acid-Mediated Tumor Proteolysis: Contribution of Cysteine Cathepsins. Neoplasia 15: 1125-1137 (2013)
- H. Kaur, S. Mao, S. Shah, D.H. Gorski, S.A. Krawetz, B.F. Sloane & R.R. Mattingly. Next-generation sequencing: a revolutionary tool for the discovery of molecular markers in breast ductal carcinoma in situ. Exp. Rev. Mol. Diagnos. 13: 151-165 (2013)
- J.M. Madden, K.L. Mueller, A. Bollig-Fischer, P. Stemmer, R.R. Mattingly & J.L. Boerner. Abrogating phosphorylation of eIF4B is required for EGFR and mTOR inhibitor synergy in triple-negative breast cancer. Breast Cancer Res. Treat. 147: 283-293 (2014)
- K.O. Osuala, M. Sameni, S. Shah, N. Aggarwal, M.L. Simonait, O.E. Franco, Y. Hong, S.W. Hayward, F. Behbod, R.R. Mattingly & B.F. Sloane. IL-6 signaling between ductal carcinoma in situ cells and cancer-associated fibroblasts mediates tumor cell growth and migration. BMC Cancer 15: 584 DOI: 10.1186/s12885-015-1576-3 (2015)
- K.J. Massey, Q. Li, N.F. Rossi, S.M. Keezer, R.R. Mattingly & D.R. Yingst. Phosphorylation of Rat Kidney Na, K-pump at Ser-938 Required for Rapid Angiotensin II-dependent Stimulation of Activity and Trafficking in Proximal Tubule Cells. Am. J. Physiol. 310: C227-C232 (2016)
- E.J. Brock, K. Ji, J.J. Reiners Jr. & R.R. Mattingly. How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization. Mini-Rev. Med. Chem. 16(5): 358-369 (2016)