Abstracts Category : Other

Endothelial notch ligands in bone marrow function and in malignancy

by Ins Sofia Martins

Tese de doutoramento, Cincias Biomdicas (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Medicina, 2017 Endothelial cells have emerged as instructive players in distinct physiological and pathological tasks, maintaining resident stem cell homeostasis, orchestrating tissue regeneration, and inducing tumor growth through the release of paracrine factors, known as angiocrine factors. In this Thesis, we explored the role of two particular angiocrine genes, Jagged 1 (Jag1) and Delta-like 4 (Dll4), in the development of prostate tumors through the recruitment of macrophages and in bone marrow (BM) regeneration following myeloablation, respectively. To address endothelial Jag1 (eJag1) function in prostate tumor progression, we used genetically engineered mouse models, in which mice that develop spontaneous prostate tumors (TRAMP) were crossed with endothelial-specific Jag1 loss- or gain-of-function mice (eJag1KO and eJag1OE). We showed that eJag1 induces macrophage recruitment into the tumors and polarization into a pro-tumoral M2 phenotype, both in vivo and in vitro. This was accompanied by a modulation in angiocrine gene expression, particularly in eJag1OE mice, and in the macrophage expression pattern. Our preliminary data thus suggest that eJag1 modulates tumor growth and angiogenesis indirectly by promoting macrophage recruitment and polarization into an M2 state. To understand how endothelial Dll4 modulation affected the BM vascular niche and hematopoiesis, we used two conditional mouse models with endothelial-specific Delta-like 4 (Dll4) loss- or gain-of-function (eDll4KO and eDll4OE) and analyzed their hematopoietic and vascular compartments with and without sub-lethal irradiation. Although the BM vascular niche was not affected by eDll4 modulation at steady state or 26 days after irradiation, by day 8 post-irradiation eDll4 induced changes in BM vessel identity, without affecting the overall BM vessel content. This modulation of the BM vascular niche was accompanied by a modulation in the angiocrine gene expression pattern and induced changes in hematopoiesis. Particularly, eDll4 levels correlated with increased erythropoiesis and decreased megakaryopoiesis and B lymphopoiesis, although it promoted the migration of B cells and megakaryocytes to the vicinity of BM sinusoids. These modifications resulted in an improvement of hematopoietic recovery both in sub-lethally irradiated eDll4KO and in lethally irradiated control mice transplanted with the BM of eDll4KO mice, suggesting that eDll4 impairs BM recovery following myeloablation and may be relevant in a setting of BM transplantation or in patients receiving chemotherapy. Taken together, our data suggests that the Notch ligands Jag1 and Dll4 may be possible targets in tumor progression and BM recovery, respectively, as their expression in endothelial cells is unfavorable in a clinical setting.Advisors/Committee Members: Dias, Srgio Jernimo Rodrigues, 1971-.