00085472can133234-sup-fig2.pdf (152.11 kB)
Supplementary Figure 2 from MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence
journal contribution
posted on 2023-03-30, 22:21 authored by Vedrana Tabor, Matteo Bocci, Nyosha Alikhani, Raoul Kuiper, Lars-Gunnar LarssonPDF file - 152K, Analysis of senescence, apoptosis and p19Arf expression in lung tissues of BRAF/MYC mice.
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ARTICLE ABSTRACT
The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence, a major barrier imposed on tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether MYC has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen-regulatable MycER, we show that tamoxifen-induced activation of MYC accelerated the onset and increased the number and size of BRAFV600E-driven adenomas in a dose-dependent manner, resulting in reduced survival. Furthermore, MYC activation leads to reduced expression of the senescence markers p16INK4A, p21CIP1, and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki67+ tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAFV600E-induced senescence-like state. Initial activation of MYC followed by tamoxifen withdrawal still resulted in an increased number of tumors and reduced survival. However, these tumors were of smaller size, showed increased expression of p16INK4A and p21CIP1, and reduced number of Ki67+ cells, indicating that MYC inactivation restores BRAFV600E-induced senescence. Surprisingly, MYC activation did not promote adenoma to carcinoma progression. This suggests that senescence suppression by MYC is a discrete step in tumor development important for sustained tumor growth but preceding malignant transformation and that additional oncogenic events are required for carcinoma development and metastasis. These findings contribute to our understanding of the neoplastic transformation process, with implications for future treatment strategies. Cancer Res; 74(16); 4222–9. ©2014 AACR.Usage metrics
Keywords
CarcinogenesisAnimal models of carcinogenesisPremalignancyTumor initiation and promotionCell CycleControl of cell cycle progressionSignal transduction pathwaysCell Death And SenescenceCellular aging and senescenceCell SignalingGene RegulationOncogenic transcription factorsLung CancerPreclinical ModelsAnimal models of cancerProgression, Invasion & MetastasisTumor progression
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