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Nature Communications May 2024Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that...
Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons' origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.
Topics: Humans; Esophageal Neoplasms; Adenocarcinoma; Organoids; Gene Amplification; DNA Methylation; Oncogenes; Male; Sequence Analysis, DNA; Clonal Evolution; Female
PubMed: 38744814
DOI: 10.1038/s41467-024-47619-4 -
The Journal of Clinical Investigation Oct 2023Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader,...
Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader, neoantigen-independent impact of carcinogens on immune responses to cancer cells remains underexplored. In this issue of the JCI, Huang et al. uncover a mechanism wherein carcinogen-treated cancer cells exhibit an inability to establish an immunosuppressive tumor microenvironment (TME) due to reduced M-CSF expression. Intriguingly, the so-called carcinogen-induced tumor-associated macrophages (TAMs) within this TME exhibited anti-tumor properties instead of the conventional immunosuppressive phenotype. This phenomenon extended to human lung cancers, as evidenced by TAM reprogramming in smokers versus nonsmokers. This study substantially advances our understanding of carcinogen-mediated effects on cancer immunogenicity, potentially redirecting approaches to cancer immunotherapy.
Topics: Humans; Carcinogens; Immunotherapy; Immunosuppressive Agents; Lung Neoplasms; Phenotype; Tumor Microenvironment; Neoplasms
PubMed: 37843275
DOI: 10.1172/JCI174319 -
Cell Death & Disease Aug 2023Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged...
Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged adjuvant intraperitoneal exposure in patients affected by either peritoneal malignancies or metastatic diseases originating from gastric, colon, kidney, and ovarian primary tumors. Mechanistically, the anticancer effects of HIPEC have been poorly explored. Herein we documented that HIPEC treatment promoted miR-145-5p expression paired with a significant downregulation of its oncogenic target genes c-MYC, EGFR, OCT4, and MUC1 in a pilot cohort of patients with ovarian peritoneal metastatic lesions. RNA sequencing analyses of ovarian peritoneal metastatic nodules from HIPEC treated patients unveils HSF-1 as a transcriptional regulator factor of miR-145-5p expression. Notably, either depletion of HSF-1 expression or chemical inhibition of its transcriptional activity impaired miR-145-5p tumor suppressor activity and the response to cisplatin in ovarian cancer cell lines incubated at 42 °C. In aggregate, our findings highlight a novel transcriptional network involving HSF-1, miR145-5p, MYC, EGFR, MUC1, and OCT4 whose proper activity contributes to HIPEC anticancer efficacy in the treatment of ovarian metastatic peritoneal lesions.
Topics: Humans; Female; Hyperthermic Intraperitoneal Chemotherapy; Genes, myc; Heat Shock Transcription Factors; Ovarian Neoplasms; Transcription Factors; Cell Line; ErbB Receptors; MicroRNAs
PubMed: 37598177
DOI: 10.1038/s41419-023-06064-9 -
Science Translational Medicine Sep 2023Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of...
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.
Topics: Humans; Animals; Mice; Oncogenes; Transcriptional Activation; Cell Nucleus; Co-Repressor Proteins; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Transcription Factors; Tumor Suppressor Proteins
PubMed: 37729434
DOI: 10.1126/scitranslmed.adi7244 -
Scientific Reports Sep 2023Disulfidptosis is a newly discovered mode of cell death. However, its relationship with breast cancer subtypes remains unclear. In this study, we aimed to construct a...
Disulfidptosis is a newly discovered mode of cell death. However, its relationship with breast cancer subtypes remains unclear. In this study, we aimed to construct a disulfidptosis-associated breast cancer subtype prediction model. We obtained 19 disulfidptosis-related genes from published articles and performed correlation analysis with lncRNAs differentially expressed in breast cancer. We then used the random forest algorithm to select important lncRNAs and establish a breast cancer subtype prediction model. We identified 132 lncRNAs significantly associated with disulfidptosis (FDR < 0.01, |R|> 0.15) and selected the first four important lncRNAs to build a prediction model (training set AUC = 0.992). The model accurately predicted breast cancer subtypes (test set AUC = 0.842). Among the key lncRNAs, LINC02188 had the highest expression in the Basal subtype, while LINC01488 and GATA3-AS1 had the lowest expression in Basal. In the Her2 subtype, LINC00511 had the highest expression level compared to other key lncRNAs. GATA3-AS1 had the highest expression in LumA and LumB subtypes, while LINC00511 had the lowest expression in these subtypes. In the Normal subtype, GATA3-AS1 had the highest expression level compared to other key lncRNAs. Our study also found that key lncRNAs were closely related to RNA methylation modification and angiogenesis (FDR < 0.05, |R|> 0.1), as well as immune infiltrating cells (P.adj < 0.01, |R|> 0.1). Our random forest model based on disulfidptosis-related lncRNAs can accurately predict breast cancer subtypes and provide a new direction for research on clinical therapeutic targets for breast cancer.
Topics: RNA, Long Noncoding; Cell Death; Myrtaceae; Oncogenes; Protein Processing, Post-Translational; Neoplasms
PubMed: 37758759
DOI: 10.1038/s41598-023-43414-1 -
Genome Biology Aug 2023In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes,...
BACKGROUND
In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC.
RESULTS
Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside.
CONCLUSION
Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.
Topics: Humans; Animals; Cats; Cattle; Dogs; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Cat Diseases; Dog Diseases; Carcinogens; Muscles
PubMed: 37635261
DOI: 10.1186/s13059-023-03026-4 -
Nature Communications Aug 2023Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53...
Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.
Topics: Animals; Humans; Male; Mice; beta Catenin; Gain of Function Mutation; Oncogene Proteins, Fusion; Prostatic Neoplasms; Proto-Oncogenes; Pyrimidines; Transcriptional Regulator ERG; Tumor Suppressor Protein p53
PubMed: 37537199
DOI: 10.1038/s41467-023-40352-4 -
Journal of Translational Medicine Aug 2023Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence....
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD58-expressing tumor cell is implicated in development of various cancers. The present study aimed to reveal the functional significance of CD58 in HCC progression and the underlying mechanisms.
METHODS
Immunohistochemical staining (IHC), and western blotting were used to detect the expression of CD58 in HCC tissues and cells. The levels of sCD58 (a soluble form of CD58) in the cell supernatants and serum were assessed by ELISA. CCK-8, colony formation, and xenograft assays were used to detect the function of CD58 on proliferation in vitro and in vivo. Transwell assay and sphere formation assay were performed to evaluate the effect of CD58 and sCD58 on metastasis and self-renewal ability of HCC cells. Western blotting, immunofluorescence (IF), TOP/FOP Flash reporter assay, and subcellular fractionation assay were conducted to investigate the molecular regulation between CD58/sCD58 and AKT/GSK-3β/β-catenin axis in HCC cells.
RESULTS
CD58 was significantly upregulated in HCC tissues. Elevation of CD58 expression correlated with more satellite foci and vascular invasion, and poorer tumor-free and overall survival in HCC patients. Higher sCD58 levels were in HCC patients' serum compared to healthy individuals. Functionally, CD58 promotes the proliferation of HCC cells in vitro and in vivo. Meanwhile, CD58 and sCD58 induce metastasis, self-renewal and pluripotency in HCC cells in vitro. Mechanistically, CD58 activates the AKT/GSK-3β/β-catenin signaling pathway by increasing phosphorylation of AKT or GSK3β signaling, promoting expression of Wnt/β-catenin target proteins and TCF/LEF-mediated transcriptional activity. Furthermore, AKT activator SC-79 or inhibitor LY294002 abolished the inhibitory effect of CD58 silencing on the proliferation, metastasis, and stemness of HCC cells.
CONCLUSIONS
Taken together, CD58 promotes HCC progression and metastasis via activating the AKT/GSK-3β/β-catenin pathway, suggesting that CD58 is a novel prognostic biomarker and therapeutic target for HCC.
Topics: Humans; beta Catenin; Carcinogens; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Glycogen Synthase Kinase 3 beta; Liver Neoplasms; Proto-Oncogene Proteins c-akt; CD58 Antigens
PubMed: 37573318
DOI: 10.1186/s12967-023-04364-4 -
Scientific Reports Sep 2023E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains...
E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains controversial and requires further research and regulation. In this study, we aimed to understand the possible hazards to humans of four compounds (formaldehyde, acetaldehyde, acrolein, and acetone) and seven heavy metals (arsenic, cadmium, manganese, lead, copper, nickel, and chromium) contained in e-cigarette liquids and aerosols and perform a health risk assessment. We searched PubMed, CNKI, and other databases for relevant literature to obtain data on organic compounds and heavy metals in e-cigarette liquids and aerosols, and conducted acute, chronic, and carcinogenic risk assessments of various chemicals by different exposure routes. This study showed that exposure to four organic compounds and seven heavy metals in e-cigarette aerosols and e-liquids can cause varying levels of health risks in humans through different routes, with the inhalation route posing a higher overall risk than dermal exposure and oral intake. Various chemicals at high exposure doses can produce health risks beyond the acceptable range. E-cigarette designers must improve their products by changing the composition of the e-liquid and controlling the power of the device to reduce the health effects on humans.
Topics: Humans; Carcinogens; Electronic Nicotine Delivery Systems; Carcinogenesis; Metals, Heavy; Arsenic
PubMed: 37749131
DOI: 10.1038/s41598-023-43112-y -
BioRxiv : the Preprint Server For... Jul 2023Extrachromosomal DNA (ecDNA) promotes cancer by driving copy number heterogeneity and amplifying oncogenes along with functional enhancers. More recent studies suggest...
Extrachromosomal DNA (ecDNA) promotes cancer by driving copy number heterogeneity and amplifying oncogenes along with functional enhancers. More recent studies suggest two additional mechanisms for further enhancing their oncogenic potential, one via forming ecDNA hubs to augment oncogene expression and the other through acting as portable enhancers to -activate target genes . However, it has remained entirely elusive about how ecDNA explores the three-dimensional space of the nucleus and whether different ecDNA have distinct interacting mechanisms. Here, by profiling the DNA-DNA and DNA-RNA interactomes in tumor cells harboring different types of ecDNAs in comparison with similarly amplified homogenously staining regions (HSRs) in the chromosome, we show that specific ecDNA interactome is dictated by ecDNA-borne nascent RNA. We demonstrate that the ecDNA co-amplifying and utilize nascent noncoding transcripts to mediate specific -activation of both ecDNA and chromosomal genes. In contrast, the ecDNA amplifying is weak in this property because of more efficient splicing to remove chromatin-associated nascent RNA. These findings reveal a noncoding RNA-orchestrated program hijacked by cancer cells to enhance the functional impact of amplified oncogenes and associated regulatory elements.
PubMed: 37547001
DOI: 10.1101/2023.07.27.550855