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Angiogenesis, and more in general deregulated tumor microenvironment (TME), is critical and required for invasive tumor growth and metastasis. Despite the development of innovative anti-angiogenic strategies, clinical trials have not replicated the results observed from preclinical models. It is therefore critical to identify new molecules and therapeutic strategies to target simultaneously different TME cell types to efficiently overcome the resistance to the therapies. Very recently therapeutic approaches that target the immune system has been shown to be promising as alternative to targeted therapy in cancer. It has been shown that Semaphorins (Semas), that transduce the signal via receptor complexes formed by neuropilin (Nrp1/2) and different plexins (Plxns), regulate tumor angiogenesis and cancer growth (8).
We have recently shown that Sema3A was an endogenous vessel normalizing and anti-tumor factor in pancreatic neuroendocrine RIP-Tag2 and cervical carcinomas (HPV16/E2) mouse models and that the treatment of these mice with adeno-associate virus (AAV)8-Sema3A, by improving cancer tissue oxygenation and extending the normalization window and blocking metastasis dissemination. More recently we observed that the treatment of PDAC mice with a highly active and uncleavable for mutated sema3A (mut-sema3A) significantly modulated the activation of tumor-associated macrophages, suggesting a role on immune cells.
The aim of this project is to evaluate the role of Sema3A and other axon guidance cues to “re-program” myeloid and T-cells from a pro-tumoral toward an anti-tumor phenotype and to block metastasis formation.
-We will treat mouse models of pancreatic, colon and breast tumor with mut-Sema3A and we will assess the effect on vessel normalization, metastasis formation and the functional changes of the different immune cell types.
-We will combine mut-Sema3A with immune-checkpoint inhibitors to activate T-cells and to identify potential synergistic effects in blocking tumor progression
-We will investigate the molecular mechanisms underlying the anti-tumor effect of mut-Sema3A (and of other axon guidance cues) by analyzing gene and miRNAs expression in the different treatment strategies and we will identify the different signaling pathways modulated among the different TME cell types.
Keywords: Tumor Angiogenesis, Tumor vessel normalization, Metastasis, Macrophages, Bone-marrow derived cells (BMDCs), Transgenic tumor mouse models, Mouse models of spontanenous tumorigenesis, , Semaphorins, T-cells, immune checkpoint inhibitors