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R-Ras protein inhibits autophosphorylation of vascular endothelial growth factor receptor 2 in endothelial cells and suppresses receptor activation in tumor vasculature.
Sawada J, Li F, Komatsu M
J Biol Chem. 2015 Mar 27;290(13):8133-45
Small molecule fluorophore and copolymer RGD peptide conjugates for ex vivo two-photon fluorescence tumor vasculature imaging.
Morales AR, Yanez CO, Zhang Y, Wang X, Biswas S, Urakami T, Komatsu M, Belfield KD
Biomaterials. 2012 Nov;33(33):8477-85
Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels.
Sawada J, Urakami T, Li F, Urakami A, Zhu W, Fukuda M, Li DY, Ruoslahti E, Komatsu M
Cancer Cell. 2012 Aug 14;22(2):235-49
Peptide-directed highly selective targeting of pulmonary arterial hypertension.
Urakami T, Järvinen TA, Toba M, Sawada J, Ambalavanan N, Mann D, McMurtry I, Oka M, Ruoslahti E, Komatsu M
Am J Pathol. 2011 Jun;178(6):2489-95
Promoter cloning and characterization of the anti-vascular proliferation gene, R-ras: role of Ets- and Sp-binding motifs.
Xu L, Komatsu M
J Biol Chem. 2009 Jan 30;284(5):2706-18
Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds.
Pilch J, Brown DM, Komatsu M, Järvinen TA, Yang M, Peters D, Hoffman RM, Ruoslahti E
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2800-4
R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis.
Komatsu M, Ruoslahti E
Nat Med. 2005 Dec;11(12):1346-50
A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.
Jan Y, Matter M, Pai JT, Chen YL, Pilch J, Komatsu M, Ong E, Fukuda M, Ruoslahti E
Cell. 2004 Mar 5;116(5):751-62
Antigen-primed CD8+ T cells can mediate resistance, preventing allogeneic marrow engraftment in the simultaneous absence of perforin-, CD95L-, TNFR1-, and TRAIL-dependent killing.
Komatsu M, Mammolenti M, Jones M, Jurecic R, Sayers TJ, Levy RB
Blood. 2003 May 15;101(10):3991-9
Masanobu Komatsu's Research Focus
Cancer, Cardiovascular Diseases
Malfunction and malformation of blood vessels are associated with a broad range of medical conditions, including cancer, cardiovascular diseases, metabolic syndromes, and age-related conditions such as macular degeneration. The ultimate goal of Dr. Komatsu’s research is to find a way to reverse the process of abnormal vessel formation or remodeling and restore normal function to these vessels. Normalization of blood vessels provides unique therapeutic opportunities. It can enhance the efficacy of cancer treatments, reestablish blood flow to ischemic hearts and limbs, avoid vascular complications in diabetes, and prevent blindness caused by damaging of retina in diabetic and elderly people.
Newly formed blood vessels undergo a maturation process during normal development and regeneration of adult tissues. It is important to understand the molecular mechanism of this process because the defects in this process will result in the formation of functionally defective blood vessels, which is typically seen in pathological lesions. Dr. Komatsu’s research is uncovering the key molecular pathways that promote normal vessel maturation process.
Masanobu Komatsu's Research Report
Blood vessel formation and maturation are regulated by the balance between pro-angiogenic and antiangiogenic signals. Dr. Komatsu’s group has recently identified a key role for the small GTPase R-Ras in promoting vessel maturation while attenuating excessive angiogenic response in pathologically regenerating vasculature. R-Ras is highly expressed in fully differentiated, quiescent vascular smooth muscle cells, endothelial cells, and pericytes of the mature adult vasculature. In contrast, the expression of R-Ras is strongly downregulated in proliferating vascular cells. Unlike prototypic oncoprotein Ras such as K-Ras, R-Ras inhibits vascular cell proliferation and invasion, and promotes vascular quiescence. Thus, R-Ras signaling primarily affects vessel remodeling and regeneration by counterbalancing vessel activation. R-Ras-deficient mice exhibit augmented vessel malformation and malfunction in tumor implants. Conversely, the gain of function of R-Ras improves vessel structure and blood perfusion and blocks plasma leakage by enhancing endothelial barrier function and pericyte association in VEGF-induced angiogenesis. Thus, R-Ras normalizes pathologically regenerating vasculature.
Regulation of tumor vessels by R-Ras*Reproduced from Sawada et al., Cancer Cell, 2012
There is currently no successful strategy for promoting vascular maturation for therapeutic purposes. The novelty of this study is centered around the new mechanism of blood vessel maturation that Dr. Komatsu’s group identified. A Ras protein typically functions as a molecular switch controlling several downstream pathways. Recent studies conducted by his laboratory suggest that R-Ras coordinates multiple signaling events in endothelial cells and pericytes to redirect nascent vessel formation from angiogenic sprouting to vessel maturation. The unique multifaceted activities of R-Ras make R-Ras pathways an important subject of investigation to search for a new strategy for manipulating blood vessel function.
Innovation in drug delivery technology
The other area of Dr. Komatsu’s research is to develop novel vascular targeting strategies for delivery of therapeutics in various human diseases. Vascular targeting technology takes advantage of unique molecular signatures of blood vessels at specific sites in the body. This technology enables direct delivery of drugs to tumors and other diseased tissues through the vascular network. Since drugs are targeted to specific sites, it is possible to enhance the drug efficacy while substantially reducing unwanted side-effects of the drugs.
Dr. Komatsu’s group recently succeeded in targeting the lung lesions of pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary vascular resistance. PAH is a serious lung disorder, which can lead to right heart failure and death. There is currently no effective treatment for PAH. Dr. Komatsu’s group used a 9 amino-acid cyclic peptide, CARSKNKDC (CAR) to selectively target PAH lesions. The unique property of CAR peptide offers a novel drug delivery system for PAH.
CAR accumulation in PAH rat lung
A, CAR accumulates in arterial smooth muscle cells and endothelium in the PAH rat lungs. B, CAR also accumulation at capillary vessel walls and the cell surface of infiltrating macrophages in the PAH lungs. C, Lower magnification showing CAR accumulation in adventitia. D, The absence of CG7C control peptide accumulation in the PAH lungs.
Upon intravenous administration, CAR peptide accumulates selectively and abundantly in the PAH lung lesions in two different rat models of PAH. The accumulation of CAR was found in all three layers (endothelium, medial smooth muscle, and adventitia) of pulmonary arteries, suggesting a therapeutic utility as a drug targeting moiety. The cell binding and penetration of CAR are both dependent on heparan sulfate expression of the cells, suggesting that the mechanism for the vascular homing and penetration to the site of hypertensive lesions is due to the expression of a unique glycosaminoglycan upregulated in the vascular bed of the PAH lung. Thus, PAH vasculature appears to express a molecular zip code not present in normal lung vasculature, and this zip code can be accessed by the CAR peptide. The deep tissue penetration property of CAR peptide is expected to enable efficient penetration of therapeutics into target tissues. More studies are underway to clinically develop CAR for intervention of PAH.
About Masanobu Komatsu
Masanobu Komatsu, Ph.D., earned his undergraduate degree in Marine Science/Biology and his Ph.D. in Cell Biology at the University of Miami, where he also received post-doctoral training in immunology. He continued his post-doctoral studies in Dr. Erkki Ruoslahti’s laboratory at Sanford-Burnham. Dr. Komatsu became Assistant Professor of Department of Pathology, University of Alabama at Birmingham in 2005 while maintaining an adjunct faculty position with NCI-Cancer Center of our institute. In 2008, Dr. Komatsu joined Sanford-Burnham full-time with a primary appointment to the Tumor Microenvironment Program, Cancer Center. He is also a member of the Cardiovascular Pathobiology Program at the Diabetes and Obesity Research Center. Dr. Komatsu holds patents for R-Ras activity in vascular cell quiescence as well as CAR peptide-mediated vascular targeting of PAH.
Board of Directors, VBS Pharmaceuticals