RESUMEN
Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.
Asunto(s)
Carcinoma de Células Escamosas , Linaje de la Célula , Células Madre Neoplásicas , Neoplasias Cutáneas , Animales , Ratones , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Células Madre Neoplásicas/patología , Análisis de la Célula Individual , Diferenciación Celular , Resistencia a Antineoplásicos/genética , Plasticidad de la Célula , Proliferación Celular , Redes Reguladoras de Genes , RNA-Seq , Regulación Neoplásica de la Expresión GénicaRESUMEN
The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas de Unión al ARN/metabolismo , Células A549 , Animales , Western Blotting , Proliferación Celular , Citometría de Flujo , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas de Unión al ARN/genéticaRESUMEN
PURPOSE OF REVIEW: High-throughput genomic sequencing has identified alterations in the gene encoding human telomerase reverse transcriptase (TERT) as points of interest for elucidating the oncogenic mechanism of multiple different cancer types, including gliomas. In gliomas, the TERT promoter mutation (TPM) and resultant overexpression of TERT are observed mainly in the most aggressive (primary glioblastoma/grade IV astrocytoma) and the least aggressive (grade II oligodendroglioma) cases. This article reviews recent research on (1) the mechanism of TERT activation in glioma, (2) downstream consequences of TERT overexpression on glioma pathogenesis, and (3) targeting TPMs as a therapeutic strategy. RECENT FINDINGS: New molecular classifications for gliomas include using TPMs, where the mutant group demonstrates the worst prognosis. Though a canonical function of TERT is established in regard to telomere maintenance, recent studies on non-canonical functions of TERT explore varied roles of telomerase in tumor progression and maintenance. Somatic alterations of the TERT promoter present a promising target for novel therapeutics development in primary glioma treatment.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Telomerasa/genética , Astrocitoma , Glioblastoma/genética , Glioma/patología , Humanos , Mutación , Regiones Promotoras GenéticasRESUMEN
Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing reactive oxygen species that, on one hand, induce nuclear factor κB signaling and expression of inflammatory cytokines, and on the other activate p53 checkpoint and senescence programs dampening the cyclin D1-pRb-E2F1 pathway. Interestingly, senescence markers are associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most NF2 tumors.
