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Nature Reviews. Cancer Oct 2023Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less... (Review)
Review
Cancer has been a leading cause of death for decades. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively inexpensive and more likely to cure. But precisely how tissues are transformed continues to provoke controversy and debate, hindering cancer prevention and early intervention strategies. Various theories of cancer origins have emerged, including the suggestion that it is 'bad luck': the inevitable consequence of random mutations in proliferating stem cells. In this Review, we discuss the principal theories of cancer origins and the relative importance of the factors that underpin them. The body of available evidence suggests that developing and ageing tissues 'walk a tightrope', retaining adequate levels of cell plasticity to generate and maintain tissues while avoiding overstepping into transformation. Rather than viewing cancer as 'bad luck', understanding the complex choreography of cell intrinsic and extrinsic factors that characterize transformation holds promise to discover effective new ways to prevent, detect and stop cancer before it becomes incurable.
Topics: Humans; Neoplasms; Oncogenes; Mutation; Stem Cells; Aging
PubMed: 37488363
DOI: 10.1038/s41568-023-00602-5 -
Cell Aug 2023Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our...
Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.
Topics: Humans; Proteogenomics; Neoplasms; Oncogenes; Cell Transformation, Neoplastic; DNA Copy Number Variations
PubMed: 37582357
DOI: 10.1016/j.cell.2023.07.014 -
Molecular Cancer Jun 2023Divergent N-methyladenosine (mA) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by mA regulators or mA RNA methylation... (Review)
Review
Divergent N-methyladenosine (mA) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by mA regulators or mA RNA methylation regulators, i.e., methyltransferases ("writers"), demethylases ("erasers"), and mA-binding proteins ("readers"). Aberrant mA modifications are associated with cancer occurrence, development, progression, and prognosis. Numerous studies have established that aberrant mA regulators function as either tumor suppressors or oncogenes in multiple tumor types. However, the functions and mechanisms of mA regulators in cancer remain largely elusive and should be explored. Emerging studies suggest that mA regulators can be modulated by epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, in cancer. This review summarizes the current roles of mA regulators in cancer. The roles and mechanisms for epigenetic modification of mA regulators in cancer genesis are segregated. The review will improve the understanding of the epigenetic regulatory mechanisms of mA regulators.
Topics: Humans; Oncogenes; Neoplasms; Acetylation; Epigenesis, Genetic; RNA
PubMed: 37391814
DOI: 10.1186/s12943-023-01810-1 -
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 -
Nature Reviews. Cancer Apr 2024Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with... (Review)
Review
Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with poor outcomes. When it was discovered over 60 years ago, ecDNA was considered to be rare, and its impact on tumour biology was not well understood. The application of modern imaging and computational techniques has yielded powerful new insights into the importance of ecDNA in cancer. The non-chromosomal inheritance of ecDNA during cell division results in high oncogene copy number, intra-tumoural genetic heterogeneity and rapid tumour evolution that contributes to treatment resistance and shorter patient survival. In addition, the circular architecture of ecDNA results in altered patterns of gene regulation that drive elevated oncogene expression, potentially enabling the remodelling of tumour genomes. The generation of clusters of ecDNAs, termed ecDNA hubs, results in interactions between enhancers and promoters in trans, yielding a new paradigm in oncogenic transcription. In this Review, we highlight the rapid advancements in ecDNA research, providing new insights into ecDNA biogenesis, maintenance and transcription and its role in promoting tumour heterogeneity. To conclude, we delve into a set of unanswered questions whose answers will pave the way for the development of ecDNA targeted therapeutic approaches.
Topics: Humans; Neoplasms; Oncogenes; DNA
PubMed: 38409389
DOI: 10.1038/s41568-024-00669-8 -
Cells Oct 2023E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most... (Review)
Review
E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most studies focus on oral and lung disease associated with e-cigarette use. However, tissue damage can be found in the cardio-vascular system and even the bladder. While the levels of carcinogenic compounds found in e-cigarette aerosols are lower than those in conventional cigarette smoke, the toxicants generated by the heat of the vaping device may include probable human carcinogens. Furthermore, nicotine, although not a carcinogen, can be metabolized to nitrosamines. Nitrosamines are known carcinogens and have been shown to be present in the saliva of e-cig users, demonstrating the health risk of e-cigarette vaping. E-cig vape can induce DNA adducts, promoting oxidative stress and DNA damage and NF-kB-driven inflammation. Together, these processes increase the transcription of pro-inflammatory cytokines. This creates a microenvironment thought to play a key role in tumorigenesis, although it is too early to know the long-term effects of vaping. This review considers different aspects of e-cigarette-induced cellular changes, including the generation of reactive oxygen species, DNA damage, DNA repair, inflammation, and the possible tumorigenic effects.
Topics: Humans; Electronic Nicotine Delivery Systems; Vaping; Respiratory Aerosols and Droplets; Carcinogens; Epithelial Cells; Nitrosamines; Carcinogenesis; Inflammation; Tumor Microenvironment
PubMed: 37947630
DOI: 10.3390/cells12212552 -
Clinical Cancer Research : An Official... Jul 2023The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human... (Review)
Review
The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human cancers. The early discovery of this oncogene, its established oncogenic relevance in diverse cancers, its substantial expression on the surface of cancer cells, and its druggable catalytic activity have made it one of the most pursued targets in the history of cancer drug development. Initiatives targeting HER2 provided the early stimulus for several transformational pharmaceutical technologies, including mAbs, tyrosine kinase inhibitors, antibody-drug conjugates, and others. The seismic impact of these efforts has been felt in treatment of many cancers, including breast, gastroesophageal, lung, colorectal, and others. This impact continues to broaden with increasing indications on the horizon and a plethora of novel agents in development. However, implementation of these therapeutic strategies has been complex. The clinical translation of every one of these classes of agents has been notable for underperformance or overperformance characteristics that have informed new lines of research providing deeper insights into the mechanistic complexities and unrealized opportunities provided by this molecular target. Despite all the successes to date, the preponderance of scientific evidence indicates that the full potential of HER2 as a target for cancer therapeutics is far greater than currently realized, and numerous lines of investigation are ongoing to deepen and broaden the scope of impact of HER2 as a signaling, homing, or immunologic target. In this review, we explore the existing data and evolving paradigms surrounding this remarkable target for cancer therapy.
Topics: Humans; Female; Receptor, ErbB-2; Antineoplastic Agents; Signal Transduction; Oncogenes; Neoplasms; Breast; Breast Neoplasms
PubMed: 36574481
DOI: 10.1158/1078-0432.CCR-22-0283 -
Journal of Hepatology Feb 2024Chronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and...
BACKGROUND & AIMS
Chronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and direct relevance to human HCC have not been established. In this study, we aimed to determine whether chronic circadian dysregulation can drive NAFLD-related carcinogenesis from human hepatocytes and human HCC progression.
METHODS
Chronic jet lag of mice with humanized livers induces spontaneous NAFLD-related HCCs from human hepatocytes. The clinical relevance of this model was analysed by biomarker, pathological/histological, genetic, RNA sequencing, metabolomic, and integrated bioinformatic analyses.
RESULTS
Circadian dysfunction induces glucose intolerance, NAFLD-associated human HCCs, and human HCC metastasis independent of diet in a humanized mouse model. The deregulated transcriptomes in necrotic-inflammatory humanized livers and HCCs bear a striking resemblance to those of human non-alcoholic steatohepatitis (NASH), cirrhosis, and HCC. Stable circadian entrainment of hosts rhythmically paces NASH and HCC transcriptomes to decrease HCC incidence and prevent HCC metastasis. Circadian disruption directly reprogrammes NASH and HCC transcriptomes to drive a rapid progression from hepatocarcinogenesis to HCC metastasis. Human hepatocyte and tumour transcripts are clearly distinguishable from mouse transcripts in non-parenchymal cells and tumour stroma, and display dynamic changes in metabolism, inflammation, angiogenesis, and oncogenic signalling in NASH, progressing to hepatocyte malignant transformation and immunosuppressive tumour stroma in HCCs. Metabolomic analysis defines specific bile acids as prognostic biomarkers that change dynamically during hepatocarcinogenesis and in response to circadian disruption at all disease stages.
CONCLUSION
Chronic circadian dysfunction is independently carcinogenic to human hepatocytes. Mice with humanized livers provide a powerful preclinical model for studying the impact of the necrotic-inflammatory liver environment and neuroendocrine circadian dysfunction on hepatocarcinogenesis and anti-HCC therapy.
IMPACT AND IMPLICATIONS
Human epidemiological studies have linked chronic circadian dysfunction to increased hepatocellular carcinoma (HCC) risk, but direct evidence that circadian dysfunction is a human carcinogen has not been established. Here we show that circadian dysfunction induces non-alcoholic steatohepatitis (NASH)-related carcinogenesis from human hepatocytes in a murine humanized liver model, following the same molecular and pathologic pathways observed in human patients. The gene expression signatures of humanized HCC transcriptomes from circadian-disrupted mice closely match those of human HCC with the poorest prognostic outcomes, while those from stably circadian entrained mice match those from human HCC with the best prognostic outcomes. Our studies establish a new model for defining the mechanism of NASH-related HCC and highlight the importance of circadian biology in HCC prevention and treatment.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Liver Neoplasms; Liver; Disease Models, Animal; Carcinogenesis; Carcinogens
PubMed: 37890720
DOI: 10.1016/j.jhep.2023.10.018 -
Nature Reviews. Clinical Oncology Oct 2023The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by... (Review)
Review
The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, the past few years have seen a paradigm shift with the emergence of several novel or later-generation TKIs with improved CNS penetrance. Such agents have promising levels of activity against brain metastases, as demonstrated by data from preclinical and clinical studies. In this Review, we describe current preclinical and clinical evidence of the intracranial activity of TKIs targeting various oncogenic drivers in patients with NSCLC, with a focus on newer agents with enhanced CNS penetration, leptomeningeal disease and the need for intrathecal treatment options. We also discuss evolving assessment criteria and regulatory considerations for future clinical investigations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Oncogenes; Patients; Blood-Brain Barrier
PubMed: 37592034
DOI: 10.1038/s41571-023-00808-4 -
Nature Genetics Dec 2023The biological functions of noncoding RNA N-methyladenosine (mA) modification remain poorly understood. In the present study, we depict the landscape of super-enhancer...
The biological functions of noncoding RNA N-methyladenosine (mA) modification remain poorly understood. In the present study, we depict the landscape of super-enhancer RNA (seRNA) mA modification in pancreatic ductal adenocarcinoma (PDAC) and reveal a regulatory axis of mA seRNA, H3K4me3 modification, chromatin accessibility and oncogene transcription. We demonstrate the cofilin family protein CFL1, overexpressed in PDAC, as a METTL3 cofactor that helps seRNA mA methylation formation. The increased seRNA mAs are recognized by the reader YTHDC2, which recruits H3K4 methyltransferase MLL1 to promote H3K4me3 modification cotranscriptionally. Super-enhancers with a high level of H3K4me3 augment chromatin accessibility and facilitate oncogene transcription. Collectively, these results shed light on a CFL1-METTL3-seRNA mA-YTHDC2/MLL1 axis that plays a role in the epigenetic regulation of local chromatin state and gene expression, which strengthens our knowledge about the functions of super-enhancers and their transcripts.
Topics: Humans; Chromatin; RNA; Epigenesis, Genetic; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Oncogenes; Methyltransferases
PubMed: 37957340
DOI: 10.1038/s41588-023-01568-8