FERRUCCI, VERONICA
PRUNE-1 DRIVES THE RECRUITMENT AND THE POLARIZATION OF TUMOUR-ASSOCIATED MACROPHAGES (TAMS) PREPARING THE SOIL FOR LUNG METASTASES IN TRIPLE NEGATIVE BREAST CANCER [Tesi di dottorato]
Università degli Studi di Milano, 2018-03-26

Tumour microenvironment is a complex network of cells, including immune cells, with a role in tumorigenesis and metastatic spread. Among the immune cells, M2-polarized Tumour-Associated-Macrophages (M2-TAMs) show immunosuppressive activities by expressing inflammatory molecules, thus promoting tumorigenesis. Triple-Negative Breast Cancer (TNBC), lacking both hormone receptors (i.e. Progesterone Receptor [PgR] and Estrogen Receptor [ER]) and Human Epidermal growth factor Receptor 2 (HER2), is associated with poor prognosis and high probability of distant metastases. In TNBC, a large number of infiltrating M2-TAMs is positively correlated to higher risk of metastases and lower rates of Disease-Free Survival” (EFS) and Overall Survival (OS). Prune-1 belongs to DHH (Asp-His-His) phosphoesterase superfamily with an exopolyphosphatase activity. The overexpression of Prune-1 is correlated with metastases and poor prognosis in several tumours including Breast Cancer (BC). Prune-1 was also found to induce Epithelial-Mesenchimal-Transition (EMT) and metastatic dissemination throught the enhancement of canonical TGF-β signaling by counterbalancing its inhibition operated by NDPK-A. Further evidences suggested that lung cancer progression is driven by Prune-1 through the canonical WNT signaling pathway in both autocrine and paracrine manner via Wnt3a cytokine secretion, thus suggesting a potential role for Prune-1 also in extracellular environment. Here, we identified Prune-1 protein as overexpressed in TNBC patients and positively correlated to lynphnode metastases, inflammatory pathways and infiltrating M2-TAMs (CD68+/CD163+). Furthermore, we developed a Genetically Engineered Mouse Model (GEMM) of metastatic TNBC over-expressing both Prune-1 and Wnt-1 in mammary glands (MMTV-Prune1/Wnt1). We found Prune-1 to recruit TAMs and to enhance their polarization toward a pro-tumorigenic M2-phenotype in the tumour microenvironment, thus promoting lung metastases in this GEMM. We also show that Prune-1 takes part to the communication between TNBC cells and TAMs through intracellular pathways activation (i.e., TGF-b and NF-kB), but also in a paracrine manner by inducing the secretion of inflammatory cytokines (e.g., IL-17F and IL-28) and modulating the exosome protein contents. Finally, we found an anti-Prune-1 drug (AA7.1) with the ability to reduce the primary tumour growth by reducing the percentage of M2-TAMs in orthotopic xenograft immunocompetent models of TNBC. In conclusion, our GEMM of metastatic TNBC driven by Prune-1 will be a useful source for future immunotherapy pre-clinical trials targeting M2-polarized TAMs within the tumour microenvironment to inhibit distant metastases in TNBC with poor prognosis.

diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/2434/563230
ZOLLO, MASSIMO
internal advisor: P. Pucci ; external advisor: K. Gevaert ; supervisor: M. Zollo ; coordinator Naples site: A. Ballabio
Settore BIO/18 - - Genetica


Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD18003162