Unveiling the effect of STING pathway restoration in MYCN-Driven Tumors

Anno
2021
Proponente -
Struttura
Sottosettore ERC del proponente del progetto
LS4_6
Componenti gruppo di ricerca
Componente Categoria
Veronica La Monica Dottorando/Assegnista/Specializzando componente il gruppo di ricerca
Giuseppe Giannini Aggiungi Tutor di riferimento (Professore o Ricercatore afferente allo stesso Dipartimento del Proponente)
Abstract

MYCN deregulation plays a key role in leading childhood and adulthood cancers. Particularly, MYCN amplification (MNA) is an independent poor prognosis marker for many tumor types, including neuroblastoma (NB), where it identifies 50% of the high-risk cases with very poor prognosis. Direct MYCN targeting is effective in preclinical models, but not yet achievable in patients. Most importantly, the mechanisms of MYCN-induced therapy resistance are largely not understood.
A number of scientific reports suggest that enduring anticancer effects are only achieved when (re)activation of immune responses is obtained, regardless of the therapeutic approach employed (chemo/radio therapy, target therapy or immune checkpoint blockade). Unfortunately, MNA NBs are mostly characterized by a "cold" phenotype, that is lack of tumor infiltrating leukocytes, low type-I interferon transcriptomics and reduced chemokine expression. In these settings, reactivation of immune responses might not be an easy task. Indeed, initial reports on the outcome of immune checkpoint blockade were rather discouraging.
By causing replication stress, PARP inhibitors are able to trigger the cytosolic DNA sensing pathway (STING pathway) and promote innate immune responses, as part of their anticancer activity. Although PARP inhibitors increase replication stress, they appeared unable to activate the STING pathway, in MNA NB tumors. Rather, our data support the hypothesis that MNA NB enforce repression of STING activity to escape its cell-intrinsic and/or immune-mediated tumor suppressive effects, which would be otherwise triggered by MYCN-dependent replication stress.
This proposal aims to provide significant proofs of principle for this hypothesis, by addressing the consequences of STING reactivation in MNA NB models.

ERC
LS4_6, LS2_5, LS3_7
Keywords:
CANCRO, BASI BIOLOGICHE DEL CANCRO, AUTOIMMUNITA¿, INFIAMMAZIONE

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