TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment.
Proc Natl Acad Sci U S A
; 118(23)2021 06 08.
Article
em En
| MEDLINE
| ID: mdl-34088837
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, which is refractory to all currently available treatments and bears dismal prognosis. About 70% of all PDAC cases harbor mutations in the TP53 tumor suppressor gene. Many of those are missense mutations, resulting in abundant production of mutant p53 (mutp53) protein in the cancer cells. Analysis of human PDAC patient data from The Cancer Genome Atlas (TCGA) revealed a negative association between the presence of missense mutp53 and infiltration of CD8+ T cells into the tumor. Moreover, CD8+ T cell infiltration was negatively correlated with the expression of fibrosis-associated genes. Importantly, silencing of endogenous mutp53 in KPC cells, derived from mouse PDAC tumors driven by mutant Kras and mutp53, down-regulated fibrosis and elevated CD8+ T cell infiltration in the tumors arising upon orthotopic injection of these cells into the pancreas of syngeneic mice. Moreover, the tumors generated by mutp53-silenced KPC cells were markedly smaller than those elicited by mutp53-proficient control KPC cells. Altogether, our findings suggest that missense p53 mutations may contribute to worse PDAC prognosis by promoting a more vigorous fibrotic tumor microenvironment and impeding the ability of the immune system to eliminate the cancer cells.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Fibrose
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Proteína Supressora de Tumor p53
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Mutação de Sentido Incorreto
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Carcinoma Ductal Pancreático
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2021
Tipo de documento:
Article