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Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.

ABSTRACT: Notch1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) and, recently, have been found in non-small-cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated Notch1 in the lung by developing a transgenic mouse model in which activated Notch1 was overexpressed in the alveolar epithelium. The initial response to activated Notch1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas appeared in the transgenic mice but failed to progress to become carcinomas. Interestingly, Myc and MycL1 were expressed in the adenomas, suggesting that selection for enhanced Myc activity may facilitate tumorigenesis. Using mice engineered to coexpress activated Notch1 and Myc, we found that supplementing Myc expression resulted in increased frequency of Notch1 intracellular domain (N1ICD)-induced adenoma formation and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by Myc and/or activated Notch1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated Notch1 substitutes for RAS activation synergistically with Myc in the development of NSCLC. These tumor models should be valuable for exploring the role of activated Notch1 in the genesis of NSCLC and for testing therapies targeting either activated Notch1 or its downstream effectors.

SUBMITTER: Allen TD

PROVIDER: S-EPMC3174331 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.

Allen Thaddeus D TD Rodriguez Elena M EM Jones Kirk D KD Bishop J Michael JM

Cancer research 20110729 18

Notch1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) and, recently, have been found in non-small-cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated Notch1 in the lung by developing a transgenic mouse model in which activated Notch1 was overexpressed in the alveolar epithelium. The initial response to activated Notch1 was proliferation and the accumulat ...[more]

PMID: 21803744

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Project description:Introduction: The PD-1/PD-L1 axis is hijacked by lung adenocarcinoma (LUAD) cells to escape immune surveillance. PD-L1 expression in LUAD is affected, among others, by the metabolic trafficking between tumor cells and the tumor microenvironment (TME). Methods: Correlation between PD-L1 expression and iron content within the TME was established on FFPE LUAD tissue samples. The effects of an iron rich microenvironment on PD-L1 mRNA and protein levels were assessed in vitro in H460 and A549 LUAD by using qPCR, western blot and flow citometry. c-Myc knockdown was performed to validate the role of this transcription factor on PD-L1 expression. The effects of iron-induced PD-L1 on T cell immune function was assessed by quantifying IFN-γ release in a co-colture system. TCGA dataset was used to analyse the correlation between PD-L1 and CD71 mRNA expression in LUAD patients. Results: In this study, we highlight a significant correlation between iron density within the TME and PD-L1 expression in 16 LUAD tissue specimens. In agreement, we show that a more pronounced innate iron-addicted phenotype, indicated by a higher transferrin receptor CD71 levels, significantly correlates with higher PD-L1 mRNA expression levels in LUAD dataset obtained from TCGA database. In vitro, we demonstrate that the addition of Fe3+ within the culture media promotes the significant overexpression of PD-L1 in A549 and H460 LUAD cells, through the modulation of its gene transcription mediated by c-Myc. The effects of iron lean on its redox activity since PD-L1 up-regulation is counteracted by treatment with the antioxidant compound trolox. When LUAD cells are co-cultured with CD3/CD28-stimulated T cells in an iron-rich culture condition, PD-L1 up-regulation causes the inhibition of T-lymphocytes activity, as demonstrated by the significant reduction of IFN-γ release. Discussion: Overall, in this study we demonstrate that iron abundance within the TME may enhance PD-L1 expression in LUAD and, thus, open the way for the identification of possible combinatorial strategies that take into account the iron levels within the TME to improve the outcomes of LUAD patients treated with anti-PD-1/PD-L1-based therapies.

Dataset Information

Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.

Publications

Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.

Similar Datasets

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