Joe W. Ramos, PhD
Deputy Director, Interim Associate Director of Administration
University of Hawaii Cancer Center
Cancer Biology Program
University of Hawaii Cancer Center
Cell and Molecular Biology
John A. Burns School of Medicine,
University of Hawaii at Manoa;
Molecular Biosciences and Bioengineering,
University of Hawaii at Manoa
- PhD, Cell Biology
University of Virginia
Scripps Research Institute
San Diego, CA
The Ramos laboratory's mission is to determine the underlying mechanisms that control cancer cell invasion and to exploit this knowledge in drug development.
Cancer Invasion and Metastasis: Cell migration is important in many physiological and pathological contexts and can be mediated by cell adhesion receptors called integrins. Integrins engage the cytoskeleton on their cytoplasmic tails through linker proteins and bind the extracellular matrix on their extracellular face. They both activate signaling pathways (outside-in) and are regulated by signaling pathways (inside-out). The Ramos lab has focused on understanding how these signaling pathways affect cell adhesion and migration with an emphasis on defining the molecular functions of the Ras/ERK MAP kinase pathway and integrins in cancer cell mobility.
The Ramos lab has defined RSK2 as a primary mediator of Ras signals to integrins and an essential regulator of integrins and cell migration. RSK2 is a kinase that regulates proliferation and adhesion and can promote metastasis. We examine RSK2 activity in both glioblastoma (Brain Cancer) and neuroblastoma (a childhood cancer originating in nerve tissue). Glioblastomas are one of the most deadly forms of cancer and can affect any age group. In glioblastoma, infiltration of primary tumor cells into the normal tissue and dispersal throughout the brain is a central challenge to successful treatment that remains unmet. Patients with glioblastoma respond poorly to the standard therapeutic regimen of radiotherapy and chemotherapy that follow tumor resection and have only a 16-month median survival. It is therefore imperative to identify new approaches to specifically attack glioblastoma cell survival, proliferation and invasion. Our lab has found that active RSK2 is essential for cell motility and invasion of patient-derived glioblastoma neurospheres. We further found that RSK2 control of migration is mediated in part by its effects on integrin-Filamin A complexes. Importantly, inhibition of RSK2 blocks invasion and combining RSK2 inhibitors with chemotherapy improves efficacy in pre-clinical in vitro neurosphere models. RSK2 is significantly upregulated in human glioblastoma patient tumors, and high RSK2 expression significantly correlates with advanced tumor stage and poor patient survival. RSK inhibitors could therefore enhance the effectiveness of existing glioblastoma treatment, and our work supports RSK2 targeting as a promising approach for novel glioblastoma therapy.
We have further shown that ERK and RSK2 activity are controlled by a protein called PEA-15. To determine the normal functions of PEA-15 we analyzed PEA-15 null mice and found that T cells from these mice undergo hyper-proliferation in response to T cell receptor activation. This is the result of increased IL-2 expression and secretion resulting from increased ERK localization in the nucleus of the T cells in the PEA15 null mice. No significant developmental defects in the immune system were found. Moreover, the mice suffer from spatial learning disabilities that overlap with those of mice lacking RSK2. In cancer we found that PEA15 effects on the ERK pathway resulted in changes in cancer cell (neuroblastoma, astrocytoma) migration and invasion as well as alterations in Ras transformation of Kidney cancer cells. This work made it clear that PEA15 can have profound effects on normal physiology. More recently our work has extended to the function of RasGRP1 in skin cancer.
Anti-cancer drug leads (GBM and Kidney) from organometallic and natural product compounds. In collaboration with several close collaborators in chemistry we have developed and defined the mechanism of action of a group of promising new compounds. In kidney cancer we were the first to show that the natural product Englerin A works by specifically activating necrosis and not other forms of cell death. We also developed a set of organometallic compounds in collaboration with Maria Contel that kill kidney cancer cells with minimal toxicity in mouse pre-clinical models. These compounds surprisingly work by targeting pro-survival and invasion kinases like RSK2 not by damaging DNA. These are among the first organometallics shown to affect kinases and the work is already widely cited for this reason. Finally we have screened natural products for effect on GBM invasion and identified the sticatmides as promising anti-invasion drug leads. This work has resulted in three provisional patents filed and one awarded in 2016 (US #9,315,531).
Overall we have used basic research on adhesion and signaling to guide development of novel new therapeutics. Currently we are examining the dysregulation of cell signaling in glioblastoma, neuroblastoma, skin cancer, and kidney cancer and developing drugs to block growth and invasion of these tumors.
- Sulzmaier FJ, Young-Robbins S, Jiang P, Geerts D, Prechtl AM, Matter ML, Kesari S, Ramos JW. (2016). RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics. Oncotarget, Nov 4. doi: 10.18632/oncotarget.13084. [Epub ahead of print] PubMed PMID: 27829215.
- Fern├índez-Gallardo J, Elie BT, Sadhukha T, Prabha S, Sana├║ M, Rotenberg SA, Ramos JW*, Contel M. (2015). Heterometallic titanium-gold complexes inhibit renal cancer cells in vitro and in vivo. Chem Sci, Sep 1;6(9):5269-5283. PubMed PMID: 27213034; PubMed Central PMCID: PMC4869729. * co-corresponding author with Dr. Contel
- Sharma A, Fonseca LL, Rajani C, Yanagida JK, Endo Y, Cline JM, Stone JC, Ji J, Ramos JW, Lorenzo PS. (2014). Targeted deletion of RasGRP1 impairs skin tumorigenesis. Carcinogenesis, 35(5):1084-91. doi: 10.1093/carcin/bgu016. PMCID: PMC4004207.
- Sulzmaier FJ, Ramos JW. (2013). RSK isoforms in cancer cell invasion and metastasis. Cancer Res, Oct 15;73(20):6099-105. doi: 10.1158/0008-5472.CAN-13-1087. (2013) PMID: 24097826 PMCID: PMC3801100
- Gawecka JE, Young-Robbins SS, Sulzmaier FJ, Caliva MJ, Heikkil├Ą MM, Matter ML, Ramos JW. (2012). RSK2 protein suppresses integrin activation and fibronectin matrix assembly and promotes cell migration. J Biol Chem, 287: 43424-43437. PMCID: PMC3527930.
- Sulzmaier FJ, Valmiki MK, Nelson DA, Caliva MJ, Geerts D, Matter ML, White EP, Ramos JW. (2012). PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D. Oncogene, Jul 26;31(30):3547-60. doi:0.1038/onc.2011.514. PMCID: PMC3295902.
- Sulzmaier FJ, Li Z, Nakashige ML, Fash DM, Chain WJ, Ramos JW. (2012). Englerin a selectively induces necrosis in human renal cancer cells. PLoS One, 7(10):e48032. doi: 10.1371/journal.pone.0048032. PubMed PMID: 23144724;PubMed Central PMCID: PMC3481555.
Publication list via PubMed
J.W. Ramos, Principal Investigator; Multiple PIs
"Regulation of Tumor Promotion by RASGRP1"
J.W. Ramos, Principal Investigator
The Ingeborg v.F. Mckee Fund
"PEA-15 Function in Bladder Cancer"