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Nature Reviews. Clinical Oncology Jan 2022The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or... (Review)
Review
The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
Topics: Genes, myc; Humans; Immune Evasion; Neoplasms; Oncogenes
PubMed: 34508258
DOI: 10.1038/s41571-021-00549-2 -
International Journal of Cancer May 2020Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme... (Review)
Review
Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme polymorphisms have been identified to increase the risk for smokers, recent epidemiological data suggest even sex-specificity as a new and additional factor. Obviously, women have a higher risk to develop lung cancer upon smoking than men. Overall, the odds ratio to develop lung cancer was almost three times greater for women than for men, DNA adduct levels were higher among females than in males and mutations in the tumor suppressor gene p53 and the proto-oncogene K-RAS were more frequently found in women than in men. A growing number of studies suggest that the interaction between tobacco carcinogens and endogenous and exogenous sex steroids may be important. Women taking hormone replacement therapy (HRT) or oral contraceptives experienced to have an increased lung cancer incidence. Epidemiologic data on HRT show a significant association between both a younger median age at lung cancer diagnosis and a shorter median survival time. Another clue is the significantly higher number of lung cancer diagnosed women who are largely premenopausal in comparison to diagnosed men in the same age or women with shorter menstrual cycles. Finally, the Coronary Drug Project (men who received estrogen preparations to reduce future cardiac events) was stopped when increased lung cancer mortality was observed in the estrogen therapy group. The present review provides a short overview and discussion on lung cancer risk and the impact thereon of sex.
Topics: Carcinogens; Female; Hormone Replacement Therapy; Humans; Incidence; Lung Neoplasms; Male; Proto-Oncogene Mas; Proto-Oncogenes; Risk Factors; Sex Factors; United States
PubMed: 31583690
DOI: 10.1002/ijc.32716 -
Journal of Hematology & Oncology Aug 2020N-methyladenosine (mA) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole... (Review)
Review
N-methyladenosine (mA) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its mA RNA methyltransferase activity. While the roles of mA modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The well-documented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.
Topics: Adenosine; Antineoplastic Agents; Binding, Competitive; Carcinogens; Drug Design; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Methylation; Methyltransferases; Models, Molecular; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Oncogenes; Protein Conformation; Protein Domains; RNA Processing, Post-Transcriptional; RNA, Neoplasm; Recombinant Fusion Proteins; Substrate Specificity; Tumor Suppressor Proteins
PubMed: 32854717
DOI: 10.1186/s13045-020-00951-w -
Nature Reviews. Cancer Apr 2022Cancer is a disease of uncontrollably reproducing cells. It is governed by biochemical pathways that have escaped the regulatory bounds of normal homeostatic balance.... (Review)
Review
Cancer is a disease of uncontrollably reproducing cells. It is governed by biochemical pathways that have escaped the regulatory bounds of normal homeostatic balance. This balance is maintained through precise spatiotemporal regulation of these pathways. The formation of biomolecular condensates via liquid-liquid phase separation (LLPS) has recently emerged as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells. Biomolecular condensates are widely observed to directly regulate key cellular processes involved in cancer cell pathology, and the dysregulation of LLPS is increasingly implicated as a previously hidden driver of oncogenic activity. In this Perspective, we discuss how LLPS shapes the biochemical landscape of cancer cells.
Topics: Humans; Neoplasms; Oncogenes
PubMed: 35149762
DOI: 10.1038/s41568-022-00444-7 -
Oncogene Apr 2021More than 25 years of research and preclinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer... (Review)
Review
More than 25 years of research and preclinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer treatment. Molecular, genetic, biochemical, and pharmacological targeting strategies have been extensively tested in vitro and in vivo, and drugs like dasatinib, initially designed to target SRC family kinases, have been found to also target EphA2 activity. Other small molecules, therapeutic targeting antibodies, and peptide-drug conjugates are being tested, and more recently, approaches harnessing antitumor immunity against EphA2-expressing cancer cells have emerged as a promising strategy. This review will summarize preclinical studies supporting the oncogenic role of EphA2 in breast cancer, lung cancer, glioblastoma, and melanoma, while delineating the differing roles of canonical and noncanonical EphA2 signaling in each setting. This review also summarizes completed and ongoing clinical trials, highlighting the promise and challenges of targeting EphA2 in cancer.
Topics: Humans; Neoplasms; Oncogenes; Receptor, EphA2
PubMed: 33686241
DOI: 10.1038/s41388-021-01714-8 -
Food and Chemical Toxicology : An... Jul 2022Tobacco and tobacco smoke contain a complex mixture of over 9500 chemical compounds, many of which have been recognized as hazardous to human health by regulatory... (Review)
Review
Tobacco and tobacco smoke contain a complex mixture of over 9500 chemical compounds, many of which have been recognized as hazardous to human health by regulatory agencies. In 2012, the U.S. Food and Drug Administration established a list of harmful and potentially harmful constituents in unburned tobacco and tobacco smoke, 79 of which are considered as carcinogens. Over the past 10 years, with advancing analytical technology, significant amounts of new data have been published, increasing our understanding of levels of carcinogens in tobacco products. The International Agency for Research on Cancer (IARC) has released 35 monographs since 2012, with an increasing number of compounds in unburned tobacco and tobacco smoke classified as carcinogens. In this paper, we provide an updated list of IARC-classified carcinogens in unburned tobacco and tobacco mainstream smoke. A total of 83 carcinogens has been identified - 37 in unburned tobacco and 80 in tobacco smoke - with their occurrence levels reported since 2012. No clear decreasing trends were observed for any of these carcinogens in recent years. Surveillance of the levels of tobacco carcinogens as well as regulatory actions are needed to ensure control of their levels so that potential reduced risks of cancer and other diseases may be achieved.
Topics: Carcinogens; Humans; Smoke; Nicotiana; Tobacco Products; Tobacco Smoke Pollution
PubMed: 35643228
DOI: 10.1016/j.fct.2022.113179 -
Molecular Cell Aug 2021The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1...
The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (mG) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of mG-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of mG-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.
Topics: Carcinogenesis; Guanosine; Humans; Methylation; Methyltransferases; Neoplasms; Oncogenes; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Transfer; tRNA Methyltransferases
PubMed: 34352207
DOI: 10.1016/j.molcel.2021.06.031 -
Nature Jun 2023Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure and the evolutionary trajectories of oncogene...
Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure and the evolutionary trajectories of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism-which we term translocation-bridge amplification-involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage-fusion-bridge cycle prevalent in some and the translocation-bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.
Topics: Female; Humans; Breast Neoplasms; Estrogen Receptor alpha; Estrogens; Gene Amplification; Oncogenes; Translocation, Genetic; Genome, Human; DNA Breaks, Double-Stranded; Organ Specificity
PubMed: 37198482
DOI: 10.1038/s41586-023-06057-w -
Toxicological Sciences : An Official... May 2015Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry... (Review)
Review
Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds.
Topics: Activation, Metabolic; Carcinogens; Cytochrome P-450 Enzyme System; Humans; Lung Neoplasms; Polycyclic Aromatic Hydrocarbons
PubMed: 25911656
DOI: 10.1093/toxsci/kfv040 -
Cell Dec 2023Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how...
Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU) revival colonic stem cells (revCSCs) to oncogene-driven LRIG1 hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRAS or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRAS collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.
Topics: Cell Differentiation; Oncogenes; Proto-Oncogene Proteins p21(ras); Signal Transduction; Stem Cells; Humans; Animals; Mice; Cell Lineage
PubMed: 38065080
DOI: 10.1016/j.cell.2023.11.004