Our lab is interested in understanding of the molecular and cellular mechanisms that underlie tissue homeostasis in health. We also aim to understand what processes go wring in disease. Combining biochemical, cell-biological and genetically engineered mouse model approaches, we focus on the role of the TAM signaling pathway (which constitutes the TAM receptors TYRO3, AXL & MERTK, and their ligands PROTEIN S (PROS1) and GAS6, from development throughout adulthood.
The members of the TAM signaling pathway are expressed by many different cell types, and play key roles in maintaining a healthy state in various physiological systems, including in the endothelial, nervous, immune and reproductive systems. Several human diseases are associated with the dysregulation of TAM signaling and its components, including blood hypercoagulation, inflammation, cancer, autoimmune disease and blindness.
In particular, we aim to understand the role of PROS1 as a TAM ligand in various physiological settings, and to understand how PROS1-mediated TAM signaling is critical to homeostatic regulation.
The role of PROS1 as a TAM agonist was controversial for many years, however it is now recognized to drive many cellular processes via TAM-receptors. Specific projects in the lab focus on the developing and adult nervous system as well as inflammatory and immune regulation by PROS1. We study the upregulation and oncogenic functions of PROS1 in tumor cells and how interaction with immune cells impact tissues in health and in disease.
Developmental focus of interest
Using advanced transgenic mouse models, we have showed that PROS1 is important for the development of blood vessels and for their healthy function in adulthood (Burstyn-Cohen et al, JCI, 2009). We aim to learn more about the role of TAM signaling in the developing vasculature and the developing nervous system, including processes which are developmental in nature but occur postnatally.
Protein S (PROS1) in development:
Protein S (PROS1) in adult homeostasis:
In the nervous system: Our lab has identified PROS1 as a multi-functional regulator of Neural Stem Cell (NSC) biology. Expressed by both embryonic and adult NSCs, PROS1 is a major factor regulating the balance between NCS proliferation versus quiescence (Zelentsova et al; Stem Cells, 2017) as well as self-renewal versus differentiation (Zelentsova-Levytzkyi et al, Front Mol Neurosci 2017). PROS1 supports the neuronal cell fate over astrocytic differentiation, thus contributing to neurogenesis. We continue to research the role of PROS1 in the nervous system, including in microglia. For more on TAM signaling in the nervous system see our recent review
In the eye: Mutations in MerTK lead to degeneration of photoreceptors, and consequent blindness in mice, rats and humans. However, the basic mechanism by which TAM signaling functions is not yet clear: what are the relevant ligand-receptor interactions? Which cells express them? In the lab, we aim to answer these questions in the eye, and to establish how PROS1 and TAM signaling are important for a healthy retina.
In cancer: TAMs were identified as proto-oncogenes, and their overexpression and hyper-activation is documented in many human cancers. However, which signals activate TAMs in cancers is not clearly understood. We identified the overexpression of PROS1 in oral cancer, and revealed it supportive role in tumor cell aggressiveness. In the same study, (Abboud-Jarrous et al, Oncotarget, 2017) we identified a novel mechanistic mode of function for PROS1, by which PROS1 overexpression regulates AXL expression levels, rather than binding and activating TAMs via the traditional ligand-receptor interactions. We continue to study PROS1-mediated interventions in various cancers, including in melanoma and the aggressive oral and lung carcinomas.
In the immune system: While TAMs are essential negative regulators of the immune system and key inhibitors of inflammation, whether PROS1 regulates the various TAM roles in immune homeostasis was not clearly understood until recently. We previously identified macrophages-expressed PROS1 plays a role in the resolution of inflammation, by driving macrophage polarization and clearing dead neutrophils from the site of inflammation (Lumbroso et al, Front Immunol, 2018). In a more recent study (Maimon et al, JCI, 2021) we unexpectedly identified an anti-metastatic role for PROS1 expressed by macrophages. This protective role of PROS1 is due to its anti-inflammatory / immune-regulatory role in macrophages. Continuing work in the lab aims to better understand how PROS1 anti-inflammatory role can be harnessed to treat diseases.
In collaboration with the Hovav lab in our institute, we investigate functional aspects of PROS1 and GAS6 in oral immunity. Collaborative work has identified both TAM ligands as regulators of oral immune homeostasis (Nassar et al, PNAS, 2017; Nassar et al, Front Immunol 2018; Tabib et al, PNAS 2018).