Solid tumors can be considered as complex organs, in which neoplastic cells are surrounded by a tumor microenvironment (TME) that consists of an extracellular matrix (ECM) and many non-transformed cell populations (e.g. fibroblasts, endothelial cells). Cancer cells shape their TME through secretion of soluble and insoluble factors, including proteins, metabolites, extracellular vesicles (EVs), and circulating nucleic acids, among which miRNAs. The cancer secretome has both local and systemic effects on tumor growth, dissemination and metastatic colonization. Several cancer-related pathways concur to reprogram the secretome, and thereby alter the TME to sustain cancer development. In human cancers, one of the most frequently mutated gene encodes for the transcription factor and tumor suppressor TP53. The majority of these mutations occur within the DNA binding domain of TP53, leading to expression of mutant p53 (mut-p53) proteins that not only lose the oncosuppressive features of the wild-type form, but may also acquire novel oncogenic properties, generally referred to as gain of function (GOF). Indeed, mut-p53 proteins are capable of promoting cancer progression, metastasis and chemoresistance. mut-p53 can exert its oncogenic functions by different mechanisms, a major one being the alteration of coding and non-coding (including miRNAs) gene expression profiles. In the laboratory where this PhD project has been developed, miR-30d was recently identified as a novel target of mut-p53 and an effector of its oncogenic functions in breast cancer cells. In an attempt to dissect the molecular mechanisms underlying the effects exerted by the mut-p53/miR-30d axis, we have demonstrated that miR-30d impacts the cancer secretome, suggesting an effect on TME remodeling. Starting from these observations, here I provided evidence that the mut-p53/miR-30d-dependent secretome is able to promote in vitro paracrine effects towards different components of TME, such as ECM, endothelial cells, fibroblasts, as well as other cancer cells. Moreover, the mut-p53/miR-30d axis also contributes to the loading of proteins within EVs. In addition, I showed that miR-30d secreted by cancer cells can exert a pro-oncogenic effect in non-transformed receiving cells and may represent a promising secreted biomarker associated with p53 status in vivo. This study provides new insights into the mechanisms by which mut-p53, through miR-30d induction, can exert pro-tumorigenic functions in a paracrine fashion, and highlights potential noninvasive biomarkers and therapeutic targets to treat tumors harboring mut-p53.
|Titolo:||Mutant p53 alters tumor microenvironment by reprogramming the cancer cell secretome via miR-30d|
|Relatore/i esterni:||Del Sal, Giannino; Capaci Valeria|
|Data di pubblicazione:||8-ott-2018|
|Appare nelle tipologie:||8.1 PhD thesis|