title: MYC synergizes with activated BRAFV600E in mouse lung tumor development by suppressing senescence.
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/BRAF(V600E)-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 BRAF(V600E) and tamoxifen-regulatable MycER, we show that tamoxifen-induced activation of MYC accelerated the onset and increased the number and size of BRAF(V600E)-driven adenomas in a dose-dependent manner, resulting in reduced survival. Furthermore, MYC activation leads to reduced expression of the senescence markers p16(INK4A), p21(CIP1), and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki67(+) tumor cells. This suggests that MYC already early during tumor formation suppresses a BRAF(V600E)-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 p16(INK4A) and p21(CIP1), and reduced number of Ki67(+) cells, indicating that MYC inactivation restores BRAF(V600E)-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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institute, Stockholm, Sweden.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Tabor
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Department of Laboratory Medicine in Lund, Lund University, Lund, Sweden.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bocci
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nyosha
authors.initials: N
authors.lastname: Alikhani
authors.affiliation: Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Raoul
authors.initials: R
authors.lastname: Kuiper
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Lars-Gunnar.Larsson@ki.se.
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D016922:Cellular Senescence; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf