Masanobu Komatsu, Ph.D.

The mission of Dr. Komatsu’s research is to take a multidisciplinary approach to address important unmet needs in various medical conditions associated with vascular disorders and abnormalities. The broad research background of the group allows them to bring multiple disciplines together to basic research, application, and technology development. The research focus of Dr. Komatsu’s laboratory is twofold. One is to investigate the molecular mechanisms of blood vessel formation, remodeling, and dysfunction. With this knowledge, they search for breakthrough solutions for the treatment of cancer, cardiovascular diseases, and vascular complications in various other conditions. The other research focus is to develop novel vascular targeting strategies for site-specific drug delivery to diseased organs and tissues.

The current research focus of the Komatsu Lab includes the role of the tumor vasculature in shaping the tumor immune landscape – in particular, the role of intratumoral high endothelial venules in facilitating tertiary lymphoid structure (TLS) formation and potentiating anti-tumor immunity. 

In a separate research program, the group investigates endothelial cell and pericyte signaling pathways responsible for the maturation and stability of blood vessels in an effort to find a way to restore normal function to pathologically regenerating or remodeling blood vessels. For the drug targeting focus area, Dr. Komatsu explores the use of specific peptides that selectively target drug delivery to the tumor vasculature, hypertensive pulmonary arteries, or inflamed endothelium in sepsis. 

High endothelial venules as gateways for lymphocyte entry into tumors

High endothelial venules (HEV) are venules specialized for recruiting naïve T and B cells into lymph nodes from the circulation. A subset of cancer patients presents lymph node-like structures called tertiary lymphoid structures (TLS) inside or at the periphery of the tumors. TLS are composed of clusters of accumulating immune cells that contain T cells, B cells, and dendritic cells surrounding HEVs. It is thought that TLS are the recruitment centers for T cells and B cells where these lymphocytes become activated locally by tumor antigens, and the HEVs serve as the main entrance for the recruitment. The densities of TLS and HEVs correlate with favorable clinical outcomes of conventional cancer therapies. The presence of TLS with B cell germinal centers predicts a significant response to anti-PD-1 immune checkpoint inhibition therapies. These clinical observations suggest that increased intratumoral HEV formation allowing lymphocyte recruitment may heighten cancer immunotherapies. The Komatsu lab is investigating the molecular mechanisms of intratumoral HEV formation and developing clinically translatable strategies to induce TLS in malignant tumors.

Regulation of blood vessel maturation and stability

Blood vessel formation and maturation are regulated by the balance between pro-angiogenic and anti-angiogenic signals. Dr. Komatsu’s group has 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. Unlike prototypic oncoprotein Ras such as K-Ras, R-Ras inhibits vascular cell proliferation and invasion and promotes vascular quiescence. R-Ras signaling primarily affects vessel remodeling and regeneration by counterbalancing vessel activation. The elevated R-Ras expression normalizes pathologically regenerating vasculature.

There is currently no successful strategy for promoting vascular maturation for therapeutic purposes. The studies conducted by Dr. Komatsu’s group showed that R-Ras coordinates multiple signaling events in endothelial cells and pericytes to redirect nascent vessel formation from angiogenic sprouting to vessel stabilization. The group also showed an important activity of R-Ras to facilitate tubulogenesis (creation of lumen) of growing vessels via non-canonical Akt pathway that stabilizes the microtubule cytoskeleton. The unique multifaceted activities of R-Ras make this Ras homolog an important subject of investigation in search of 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 target-specific drug delivery. 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 or 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 the adverse side effects of the drugs. 

Dr. Komatsu’s group 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 the CAR peptide offers a novel drug delivery system for PAH.