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Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.Cancer Discovery Dec 2021Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel...
UNLABELLED
Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.
SIGNIFICANCE
The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Gene Fusion; Genes, myc; Lung Neoplasms; Mice; Proto-Oncogene Proteins c-myc; Small Cell Lung Carcinoma; Telomere-Binding Proteins
PubMed: 34344693
DOI: 10.1158/2159-8290.CD-21-0441 -
Clinical and Translational Medicine Aug 2022
Topics: Ferroptosis; Genes, myc; Humans; N-Myc Proto-Oncogene Protein; Neuroblastoma
PubMed: 35908258
DOI: 10.1002/ctm2.963 -
Journal of Gastroenterology and... Apr 2018Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in... (Review)
Review
Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in intercellular communication. Exosomes derived from colorectal cancer (CRC) cells are related to oncogenesis, tumor cell survival, chemo-resistance, and metastasis. The role of the exosomes in these processes involves the transfer of proteins, RNAs, or mutant versions of proto-oncogenes to the target cells. In recent years, great efforts have been made to identify useful biomarkers in CRC exosomes for diagnosis, prediction of prognosis, and treatment response. This review focuses on recent studies on CRC exosomes, considering isolation, cargo, biomarkers, and the effects of exosomes on the development and progression of CRC, including resistance to antitumor therapy.
Topics: Biomarkers, Tumor; Carcinogenesis; Colorectal Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Exosomes; Humans; Mutation; Neoplasm Proteins; Prognosis; Protein Transport; Proto-Oncogenes; RNA, Neoplasm
PubMed: 29156509
DOI: 10.1111/jgh.14049 -
Cold Spring Harbor Perspectives in... Nov 2018Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the... (Review)
Review
Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors.
Topics: Antineoplastic Agents; Extracellular Signal-Regulated MAP Kinases; Genes, ras; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Mutation; Neoplasms; Proto-Oncogene Proteins B-raf; raf Kinases
PubMed: 29440321
DOI: 10.1101/cshperspect.a031492 -
Aging Dec 2015
Topics: Animals; Brain; Gene Expression Regulation, Developmental; Genes, fos; Mice; Mice, Knockout; Neurons; Transcription Factor AP-1
PubMed: 26684501
DOI: 10.18632/aging.100862 -
Aging Jul 2015
Topics: Genes, myc; Humans; Proto-Oncogene Proteins c-myc; RNA, Untranslated; Transcriptome
PubMed: 26186937
DOI: 10.18632/aging.100777 -
Nature Communications Jan 2024Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic...
Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins p21(ras); Allelic Imbalance; Genes, ras; Cell Transformation, Neoplastic; Colorectal Neoplasms; Mutation; Tumor Microenvironment
PubMed: 38168062
DOI: 10.1038/s41467-023-44342-4 -
International Journal of Molecular... Jun 2019Energetically speaking, ribosome biogenesis is by far the most costly process of the cell and, therefore, must be highly regulated in order to avoid unnecessary energy... (Review)
Review
Energetically speaking, ribosome biogenesis is by far the most costly process of the cell and, therefore, must be highly regulated in order to avoid unnecessary energy expenditure. Not only must ribosomal RNA (rRNA) synthesis, ribosomal protein (RP) transcription, translation, and nuclear import, as well as ribosome assembly, be tightly controlled, these events must be coordinated with other cellular events, such as cell division and differentiation. In addition, ribosome biogenesis must respond rapidly to environmental cues mediated by internal and cell surface receptors, or stress (oxidative stress, DNA damage, amino acid depletion, etc.). This review examines some of the well-studied pathways known to control ribosome biogenesis (PI3K-AKT-mTOR, RB-p53, MYC) and how they may interact with some of the less well studied pathways (eIF2α kinase and RNA editing/splicing) in higher eukaryotes to regulate ribosome biogenesis, assembly, and protein translation in a dynamic manner.
Topics: Animals; Biomarkers; Cell Cycle; Disease Susceptibility; Eukaryotic Initiation Factor-2; Extracellular Space; Genes, myc; Humans; Phosphatidylinositol 3-Kinases; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; RNA Editing; RNA Splicing; RNA, Ribosomal; Ribosomes; Signal Transduction; Stress, Physiological; TOR Serine-Threonine Kinases; Transcription, Genetic
PubMed: 31163577
DOI: 10.3390/ijms20112718 -
The Journal of Biological Chemistry Oct 2022Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of...
Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of FAM83A in other physiological processes is not well known. Here, we report a novel function of FAM83A in adipocyte differentiation. We used an adipocyte-targeting fusion oligopeptide (FITC-ATS-9R) to deliver a FAM83A-sgRNA/Cas9 plasmid to knockdown Fam83a (ATS/sg-FAM83A) in white adipose tissue in mice, which resulted in reduced white adipose tissue mass, smaller adipocytes, and mitochondrial damage that was aggravated by a high-fat diet. In cultured 3T3-L1 adipocytes, we found loss or knockdown of Fam83a significantly repressed lipid droplet formation and downregulated the expression of lipogenic genes and proteins. Furthermore, inhibition of Fam83a decreased mitochondrial ATP production through blockage of the electron transport chain, associated with enhanced apoptosis. Mechanistically, we demonstrate FAM83A interacts with casein kinase 1 (CK1) and promotes the permeability of the mitochondrial outer membrane. Furthermore, loss of Fam83a in adipocytes hampered the formation of the TOM40 complex and impeded CK1-driven lipogenesis. Taken together, these results establish FAM83A as a critical regulator of mitochondria maintenance during adipogenesis.
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes, White; Adipogenesis; Casein Kinase I; Cell Differentiation; Mitochondria; Proto-Oncogenes; Neoplasm Proteins
PubMed: 35931121
DOI: 10.1016/j.jbc.2022.102339 -
Journal of Cellular Biochemistry Nov 2018Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is...
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2 ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2 ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.
Topics: Analysis of Variance; Animals; Bone Density; Bone Remodeling; Calcification, Physiologic; Cancellous Bone; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteoblasts; Osteoclasts; Osteogenesis; Osteosarcoma; Proto-Oncogene Mas; Proto-Oncogene Proteins c-mdm2; Proto-Oncogenes
PubMed: 30011084
DOI: 10.1002/jcb.27133