Rosalie Sears, PhD - Professor
Professor, Dept. of Molecular and Medical Genetics
Translational Science Director, Brenden-Colson Center for
GI Program Leader, Knight Cancer Institute
Oregon Health & Science University
Mail Code, L103A, Mac Hall 2141
3181 SW Sam Jackson Park Rd.
Portland, OR 97239
PH: (503) 494-6885
Fax: (503) 494-4411
The Sears lab studies cellular signaling pathways that control tumor cell phenotype, with a focus on their regulation of the c-Myc oncoprotein and how this impacts its expression, transcriptional activity, and regulation of cell fate. c-Myc is constitutively overexpressed in the majority of human tumors and studies have demonstrated that this affects both tumor cell state (proliferation, differentiation, metabolism) as well as cross-talk with the tumor microenvironment affecting immune surveillance and vasculature. We have identified a complex signaling pathway that coordinately regulates c-Myc turnover, via ubiquitin-mediated degradation, and its DNA binding and transcriptional activity. This pathway targets two conserved phosphorylation sites in c-Myc, Threonine 58 (T58) and Serine 62 (S62), which have opposing effects on c-Myc stability and activity (see figure 1). Serine 62 phosphorylation by Ras-activated ERK stabilizes Myc, and upon Pin1-mediated isomerization, activates pro-growth target gene expression. Threonine 58 phosphorylation by GSK3b, which is inhibited by Ras-activated PI(3)K, stimulates Myc ubiquitin-mediated degradation by facilitating a second Pin1-mediated isomerization event, allowing removal of the stabilizing Serine 62 phosphate by the conformation sensitive protein phosphatase 2A-B56a (PP2A-B56a). Phosphorylation at Threonine 58 also recruits the Myc E3 ubiquitin ligase, SCFFbw7, which then directs Myc poly-ubiquitination and degradation.
We have discovered that c-Myc is aberrantly phosphorylated and stabilized in many tested human cancer cell lines and primary patient tumor samples, with elevated Serine 62 phosphorylation and reduced Threonine 58 phosphorylation. We have generated genetically engineered mice to study the in vivo role of altered c-Myc phosphorylation, which have demonstrated the increased tumorigenic properties of S62 phosphorylated c-Myc. This paradigm shift in our understanding of what it means to activate c-Myc in cancer cells provides a pathway for therapeutic intervention targeting post-translational activation of c-Myc in human cancer. We are testing two promising therapeutics targeting this pathway for the treatment of breast and pancreatic cancer in vivo using orthotopic cancer cell line xenografts, patient derived xenografts, and novel spontaneous mammary gland and pancreas cancer mouse models we have developed. In addition, we are particularly focused on how these and other targeted therapeutics can be used to overcome phenotypic heterogeneity in breast and pancreatic cancer.
In 2013, the Brenden-Colson Center for Pancreatic Care (BCCPC) was established at OHSU with the goal to build a world-class pancreatic disease center, with a strong basic and translational research program that will feed clinical trial development towards clinical impact. Dr. Sears is co-director of this center. The BCCPC, in partnership from Organovo, Inc., obtained a NovoGen MMX 3D Bioprinter, which enables the creation of 3D tissues. The Sears lab is using the Bioprinter to accurately reproduce native tissues, including dense cellularity and the presence of multiple cell types with spatially defined architecture. Creation is automated and highly reproducible, consistently yielding tissues with in vivo-like micro-architecture.
Fig. 2 - Bioprinted cancer tissue where stromal cells (red) surround a pocket of cancer cells (green). Endothelial cells in the tissue (yellow) form networks throughout the tissue.
1. Janghorban, M., A. S. Farrell, B. L. Allen-Petersen, C. Pelz, Colin J. Daniel, J. Oddo, E. M. Langer, D. J. Christensen, and R. C. Sears. 2014. Targeting c-MYC by
Antagonizing PP2A Inhibitors in Breast Cancer. PNAS, In Press
2. Farrell, A. S., B. Allen-Petersen, C. J. Daniel, X. Wang, Z. Wang, S. Rodriguez, S. Impey, J. Oddo, M.P. Vitek, C. Lopez, D. J. Christensen, B. Sheppard, and R. C. Sears*. 2014. Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer. Molecular Cancer Research, 12(6): 924-39.
3. Agarwal, A.*, R.C. Sears, B Druker, D. Christensen. 2013. SET antagonism enhances efficacy of tyrosine kinase inhibitors in myeloid leukemias. Clinical Cancer Research, 20(8):2092-103.
4. Farrell, A. S., C. J. Daniel, X. Zhang, X. Wang, C. Morgan, C. Pelz, S. Impey, and R. C. Sears*. 2013. A novel post-translational mechanism controlling the oncogenic activity of c-Myc is enhanced in poor outcome breast cancer. Mol. Cell. Biol., 33(15):2930-2949.
5. Tibbitts, D. C., J. R. Escamilla-Powers, X. Zhang, R. C. Sears*. Studying c-Myc serine 62 phosphorylation in leukemia cells: concern over antibody cross-reactivity. Blood, 2012 May 31;119(22):5334-5
6. Zhang, X., A. Farrell, C. Daniel, H. Arnold, C. Scanlan, B. Laraway, M. Janghorban, L. Lum, D. Chen, M. Troxell, and R. C. Sears*. 2011. Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression. Proc Natl Acad Sci USA, 2012 Feb 21;109(8):2790-5.
7. Wang, X., M. Cunningham, X. Zhang, S. Tokarz, B. Laraway, M. Troxell and R. C. Sears*. 2011. Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland. Cancer Research, 71:925-936.
Dr. Sears received her Bachelors degree in Biology from Reed College (1986), Portland Oregon. She received her Ph.D. in Cell Biology from Vanderbilt University (2003), Nashville Tennessee, and conducted her post-doctoral studies at Duke University in the Genetics Department. Dr. Sears is a full professor in the Department of Molecular and Medical Genetics at Oregon Health & Science University. She is the Translational Science Director of the Brenden-Colson Center for Pancreatic Care, and the GI Program Leader in the Knight Cancer Institute. Dr. Sears has received funding from the National Institutes of Health, the Department of Defense, the Susan G. Komen Foundation, the Leukemia and Lymphoma Foundation, as well as several other private foundations. She has received both research and business innovation awards in the areas of cancer biology, therapeutics, and technology advancement.