CDH5

'Merlin' serves as a gatekeeper in new blood vessel formation. Merlin suppresses internalization of VEGFR2, which is important for the formation of 'tip' endothelial cells. Blood vessels are the body's essential architecture that exists in order to nurture cells with sufficient nutrients and oxygen. Angiogenesis, or the formation of new blood vessels, is of great research interest in cancer medicine. As tumors need to generate new blood vessels to grow, inhibiting angiogenesis has been suggested as a promising approach to treating cancer. Sprouting angiogenesis is the process where new sprouts are formed from pre-existing vessels. The key biological process in sprouting angiogenesis involves balancing the formation of 'tip' and 'stalk' endothelial cells (ECs). This is a process called tip-stalk specification. Tip ECs are highly motile with many long and dynamic filopodia, whereas stalk ECs are highly proliferative with fewer filopodia. These functionally distinct tip and stalk cells coordinate into a branched network of vessels for sprouting angiogenesis. Morphologically, tip EC induction is the foremost step for sprouting angiogenesis. The formation of the tip ECs is induced by a pathway called vascular endothelial growth factor (VEGF)-A (given as VEGF hereafter) signaling. Molecularly, intracellular activation of VEGFR2 signaling is initiated by ligand-induced, clathrin-dependent VEGFR2 internalization. Scientists have long been curious how one particular EC ends up possessing higher VEGFR2 signaling activity than its neighbors and is thus fated to become a tip EC during sprouting angiogenesis. Led by Dr. BAE Jung Hyun and Professor KOH Gou Young, researchers at the Center for Vascular Research within the Institute for Basic Science (IBS) in Daejeon, South Korea discovered that a protein called Merlin is indispensable for tip EC induction by regulating intracellular VEGFR2 downstream signaling during sprouting angiogenesis. Merlin, encoded by the neurofibromatosis type-2 gene NF2, has been known for quite a while to function as a tumor suppressor. It is ubiquitously expressed in all types of cells and acts as a membrane-associated protein, which plays a gatekeeping role in signal transduction from membrane receptors in a cell density-dependent manner. Nevertheless, it has not been investigated whether endothelial Merlin is essential in sprouting angiogenesis and, in detail, which intracellular signaling is regulated by endothelial Merlin. The researchers showed that the density of the EC in the environment was the key factor. When the localization and density of Merlin in the cells under low or high culture density were compared, Merlin in the high cell density culture was able to better form complex with VEGFR2. The researchers showed that this is due to the fact that the presence of VE-cadherin, a cell-to-cell junction protein, is required for Merlin and VEGFR2 to form a complex with one another. This formation of the Merlin-VEGFR2 complex suppresses VEGFR2 internalization, thereby suppressing the pathway. In contrast, Merlin in a low-density ECs environment with relatively low VE-cadherin density allows a high level of VEGFR2 signaling and ERK activation, which leads to tip EC induction. The researchers investigated the importance of cell density on Merlin-VEGFR2 complex formation by studying Merlin in its normal form, inactive phosphorylated form (pMerlin (S518), short for phosphorylated Merlin at Serine 518), and a variant that cannot be phosphorylated. It was shown that Merlin engages in physical interaction with VEGFR2 and VE-cadherin in dense culture, which has a low pMerlin (S518), but Merlin does not engage in this interaction in sparse culture, with a high pMerlin (S518) in cultured ECs. Thus, the interaction between Merlin and VEGFR2 depends on pMerlin (S518), which is regulated by cell density. "The role of Merlin in EC fulfills the missing piece for sprouting angiogenesis. Sprouting angiogenesis should be regulated by the coordinated balance of promotion and inhibition of signaling through Merlin," explains the first author, BAE Jung Hyun. The researchers further demonstrated that Merlin also plays a gatekeeping role in maintaining capillary integrity and proper angiogenesis by suppressing the unnecessary formation of filopodia and sprouting from the adult vessels in normal tissues and tumors. When the Merlin was depleted in the EC, the researchers found that an excessive amount of non-functional vessels are formed in the tumor model, which enhances tumor necrosis and reduces tumor growth. Merlin-deficient mice implanted with human lung cancer showed an impressive 80.6% reduction in tumor growth after 3 weeks in comparison to regular mice. Likewise, adult vessels in the thyroid gland and small intestine showed an increased number of filopodia in Merlin-deleted mice in comparison to wild-type mice. Director KOH Gou Young of the Center for Vascular Research summarized, "Our study showed that Merlin is mainly localized at the cell membrane in vascular ECs, interacts with VEGFR2 and VE-cadherin, and plays a negative role in VEGFR2 intracellular downstream signaling by suppressing VEGFR2 internalization. As a consequence, endothelial Merlin can be seen as a gatekeeping regulator for tip EC induction in retinal sprouting angiogenesis during postnatal development, for formations of filopodia and sprouts in matured and established capillary ECs of adults, and for tip cell formation and proper tumor vessel construction in tumor vessels."

LEXINGTON, Mass., March 3, 2021 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx), a commercial biotech company, announces a licensing and collaboration agreement with Munich-based SIRS Theraputics and Vienna-based F4 Pharma to support the development of FX-06, a synthetic peptide that has a broad spectrum of potential indications. The partnership will focus on exploring potential collaborations with the U.S. Government to develop FX-06 as a medical countermeasure against high priority threats for which there are significant unmet needs. SIRS and F4 Pharma are developing FX-06 in diseases associated with capillary leak with a current focus on treating patients with COVID-19. FX-06 is a fibrin-derived peptide (peptide Bβ 15–42) that binds to VE-Cadherin, thereby restoring the barrier function of the endothelium. Based upon its ability to restore barrier function, prevent vascular leak and leukocyte transmigration and reduce vasoconstriction, FX-06 is anticipated to mitigate the duration and severity of hemorrhage and accelerate recovery from barrier integrity loss resulting from pandemic and biological threats, such as COVID-19 and hemorrhagic fevers, as well as chemical agents and acute radiation exposure. "We are excited to work with Partner Therapeutics, given their impressive track record in late stage development in the area of medical countermeasures for bio-threats and their industry experienced development team. In collaboration with Partners Therapeutics we are focused on exploring FX-06 in areas of high interest and medical need," said Anne Burger, CEO of SIRS Therapeutics. Petra Wülfroth, CSO and co-founder of F4 Pharma "The current SARS-CoV-2 pandemic has highlighted the public vulnerability caused by viruses, however, other biological or chemical threat agents can also evolve into a major public concern. FX-06 has a broad applicability in diseases and pathological conditions caused by systemic inflammation and increased permeability of the blood vessels." She added, "We believe its mechanism of action makes it promising tool to protect people." "FX-06 has been shown to counteract vascular leak and its fatal consequences from a variety of causes including thrombin, oxygen radicals, bacteria and viruses. Efficacy has been demonstrated in animal models of septic shock, hemorrhagic shock, dengue shock syndrome, capillary leak, hemorrhagic fever, reperfusion injury, transplantation and acute lung injury," said Debasish Roychowdhury, MD, Chief Technology Officer at Partner Therapeutics. "We look forward to the opportunity to further explore the utility of FX-06 as a solution to the high priority threats identified by the U.S. Government." "We look forward to the opportunity to work with our partners at SIRS and F4 Pharma to advance the development of FX06 as a potentially important treatment for COVID-19 as well as future pandemic threats and unmet needs for medical countermeasures," said John McManus, Chief Business Officer at Partner Therapeutics. "We believe that FX-06's activity in both animal and human models could make it a powerful potential tool for both known and unknown threats." PTx plans to accelerate the development of FX-06 as a state-of-the-art pharmaceutical prototype MCM for the treatment of multiple biothreats of interest to the US Government. PTx is currently conducting two clinical trials of Leukine®, an FDA-approved immune modulator, in patients with COVID-19 under a $35 million development contract with the Department of Defense Joint Program Executive Office – Chemical Biological Radiological Nuclear (JPEO-CBRN). Leukine was FDA-approved for the treatment of the hematological damage due to acute radiation exposure under an advanced development contract with the Biomedical Advanced Research and Development Authority (BARDA) and is held in the Strategic National Stockpile for use in this indication. ABOUT PARTNER THERAPEUTICS PTx is an integrated biotechnology company focused on the development and commercialization of late-stage therapeutics that improve health outcomes in the treatment of cancer and other serious diseases. The company believes in delivering products and supporting medical teams with the purpose of achieving superior outcomes for patients and their families. Visit ABOUT SIRS THERAPEUTICS SIRS Therapeutics GmbH is a development stage biopharmaceutical company that develops FX06, a fibrin-derived peptide for the treatment of diseases related to capillary leakage e.g., ARDS in patients with underlying COVID-19 infection. The Company was founded with initial investments from Wellington Partners in 2020 and is located in Germany. Visit ABOUT F4 PHARMA F4 Pharma is a privately owned Austrian biotechnology company focusing on the development of the platform molecule FX06 in several indications with high unmet medical need. It is the intention of F4 Pharma to provide a safe and efficacious therapy to patients and physicians in critical disease situations in intensive care. Visit ABOUT FX-06 The endothelium, i.e. the inner layer of the blood vessels, plays an important role in the homeostasis between the blood within the vessel and the surrounding tissue. In many pathological disease situations, this well-balanced equilibrium is disturbed causing an increased permeability of the blood vessel and allowing inflammatory cells to invade into the surrounding tissue. The synthetic peptide FX06 binds to the contact points between the cells, normalizes increased permeability and reduces the systemic inflammation of the endothelium.