RESUMO
Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3Δ/Δ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.
Assuntos
Células Epiteliais/metabolismo , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator de Transcrição STAT3/metabolismo , Caracteres Sexuais , Transdução de Sinais , Animais , Feminino , Deleção de Genes , Interleucina-6/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Modelos Biológicos , Neutrófilos/metabolismo , Receptores de Estrogênio/metabolismo , Microambiente TumoralRESUMO
The activity of many oncogenic proteins depends on the molecular chaperone Hsp90. Recent studies indicate that tumorigenesis is associated with increased expression of chaperones, such as Hsp90. However, little is known about the isoform dependence and cochaperone contribution on tumor formation. Here we report the first systematic expression profiling for Hsp90alpha and Hsp90beta, the cochaperones Aha1, Cdc37, p23, Tpr2, and the Hsp90 dependent transcription factor HSF1 in a set of different tumor tissue samples. We find that in 10 out of 17 human tumors the expression level of at least one Hsp90 or Hsp90 cochaperone protein is significantly elevated. However, individual tumors show unique patterns of expression. Furthermore, Hsp90alpha and Hsp90beta expression levels are not related. Our results suggest that expression profiling of Hsp90alpha and Hsp90beta and its cochaperone proteins may be useful for cancer diagnosis and prognosis as well as for tailoring of drugs that interfere with the Hsp90 system in a tumor specific manner.