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Gastroenterology Dec 2020The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of...
BACKGROUND AND AIMS
The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.
METHODS
By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.
RESULTS
Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.
CONCLUSIONS
This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Computational Biology; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Liver Neoplasms; Male; Mice; Mice, Transgenic; Proto-Oncogenes; Tumor Escape; Tumor Microenvironment
PubMed: 32814112
DOI: 10.1053/j.gastro.2020.08.015 -
Nature May 2024Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations. RMC-7977 is a...
Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.
Topics: Animals; Female; Humans; Mice; Antineoplastic Agents; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; DNA Copy Number Variations; Drug Resistance, Neoplasm; Genes, myc; Guanosine Triphosphate; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Treatment Outcome; Xenograft Model Antitumor Assays; Mutation
PubMed: 38588697
DOI: 10.1038/s41586-024-07379-z -
Nature Communications Dec 2022Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in...
Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. Kras mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.
Topics: Animals; Mice; Beclin-1; Genes, ras; Lung Neoplasms; Mutation; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53; Ubiquitin-Specific Proteases
PubMed: 36528652
DOI: 10.1038/s41467-022-35557-y -
International Journal of Molecular... Dec 2023Neuroblastoma (NB), a childhood cancer arising from the neural crest, poses significant clinical challenges, particularly in cases featuring amplification of the... (Review)
Review
Neuroblastoma (NB), a childhood cancer arising from the neural crest, poses significant clinical challenges, particularly in cases featuring amplification of the oncogene. Epigenetic factors play a pivotal role in normal neural crest and NB development, influencing gene expression patterns critical for tumorigenesis. This review delves into the multifaceted interplay between MYCN and known epigenetic modifications during NB genesis, shedding light on the intricate regulatory networks underlying the disease. We provide an extensive survey of known epigenetic mechanisms, encompassing DNA methylation, histone modifications, non-coding RNAs, super-enhancers (SEs), bromodomains (BET), and chromatin modifiers in -amplified (MNA) NB. These epigenetic changes collectively contribute to the dysregulated gene expression landscape observed in MNA NB. Furthermore, we review emerging therapeutic strategies targeting epigenetic regulators, including histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi), and DNA methyltransferase inhibitors (DNMTi). We also discuss and summarize current drugs in preclinical and clinical trials, offering insights into their potential for improving outcomes for MNA NB patients.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genes, myc; N-Myc Proto-Oncogene Protein; Neuroblastoma
PubMed: 38069407
DOI: 10.3390/ijms242317085 -
Genome Research Apr 2022The oncogene encodes for the MYC protein and is frequently dysregulated across multiple cancer cell types, making it an attractive target for cancer therapy....
The oncogene encodes for the MYC protein and is frequently dysregulated across multiple cancer cell types, making it an attractive target for cancer therapy. overexpression leads to MYC binding at active enhancers, resulting in a global transcriptional amplification of active genes. Because super-enhancers are frequently dysregulated in cancer, we hypothesized that MYC preferentially invades into super-enhancers and alters the cancer genome organization. To that end, we performed ChIP-seq, RNA-seq, circular chromosome conformation capture (4C-seq), and Spike-in Quantitative Hi-C (SIQHiC) on the U2OS osteosarcoma cell line with tetracycline-inducible overexpression in U2OS cells modulated histone acetylation and increased MYC binding at super-enhancers. SIQHiC analysis revealed increased global chromatin contact frequency, particularly at chromatin interactions connecting MYC binding sites at promoters and enhancers. Immunofluorescence staining showed that MYC molecules formed punctate foci at these transcriptionally active domains after overexpression. These results demonstrate the accumulation of overexpressed MYC at promoter-enhancer hubs and suggest that MYC invades into enhancers through spatial proximity. At the same time, the increased protein-protein interactions may strengthen these chromatin interactions to increase chromatin contact frequency. siRNA knockdown in -overexpressed U2OS cells demonstrated that removal of architectural proteins can disperse MYC and abrogate the increase in chromatin contacts. By elucidating the chromatin landscape of MYC-driven cancers, we can potentially target MYC-associated chromatin interactions for cancer therapy.
Topics: Binding Sites; Cell Line; Chromatin; Enhancer Elements, Genetic; Genes, myc; Promoter Regions, Genetic
PubMed: 35115371
DOI: 10.1101/gr.276313.121 -
BMC Genomics Jun 2022The R2R3-MYB transcription factor is one of the largest gene families in plants and involved in the regulation of plant development, hormone signal transduction, biotic...
BACKGROUND
The R2R3-MYB transcription factor is one of the largest gene families in plants and involved in the regulation of plant development, hormone signal transduction, biotic and abiotic stresses. Tobacco is one of the most important model plants. Therefore, it will be of great significance to investigate the R2R3-MYB gene family and their expression patterns under abiotic stress and senescence in tobacco.
RESULTS
A total of 174 R2R3-MYB genes were identified from tobacco (Nicotiana tabacum L.) genome and were divided into 24 subgroups based on phylogenetic analysis. Gene structure (exon/intron) and protein motifs were especially conserved among the NtR2R3-MYB genes, especially members within the same subgroup. The NtR2R3-MYB genes were distributed on 24 tobacco chromosomes. Analysis of gene duplication events obtained 3 pairs of tandem duplication genes and 62 pairs of segmental duplication genes, suggesting that segmental duplications is the major pattern for R2R3-MYB gene family expansion in tobacco. Cis-regulatory elements of the NtR2R3-MYB promoters were involved in cellular development, phytohormones, environmental stress and photoresponsive. Expression profile analysis showed that NtR2R3-MYB genes were widely expressed in different maturity tobacco leaves, and however, the expression patterns of different members appeared to be diverse. The qRT-PCR analysis of 15 NtR2R3-MYBs confirmed their differential expression under different abiotic stresses (cold, salt and drought), and notably, NtMYB46 was significantly up-regulated under three treatments.
CONCLUSIONS
In summary, a genome-wide identification, evolutionary and expression analysis of R2R3-MYB gene family in tobacco were conducted. Our results provided a solid foundation for further biological functional study of NtR2R3-MYB genes in tobacco.
Topics: Amino Acid Sequence; Gene Expression Regulation, Plant; Genes, myb; Multigene Family; Phylogeny; Plant Proteins; Nicotiana
PubMed: 35681121
DOI: 10.1186/s12864-022-08658-7 -
Disease Models & Mechanisms Feb 2022The term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of...
The term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway. In defining a RASopathy syndrome, one needs to consider the complex nature of the RAS/MAPK pathway, the numerous genes and regulatory components involved, its crosstalk with other signaling pathways and the phenotypic spectrum among these syndromes. Three main guiding principles to the definition should be considered. First, a RASopathy is a clinical syndrome with overlapping phenotypic features caused by germline pathogenic variants associated with the RAS/MAPK pathway. Second, a RASopathy is caused by multiple pathogenetic mechanisms, all of which lead to a similar outcome of RAS/MAPK pathway activation/dysregulation. Finally, because a RASopathy has dysfunctional germline RAS/MAPK pathway activation/dysregulation, it may, therefore, be amenable to treatment with pathway modulators.
Topics: Genes, ras; Humans; Mitogen-Activated Protein Kinases; Signal Transduction; Syndrome
PubMed: 35103797
DOI: 10.1242/dmm.049344 -
Cancer Medicine Apr 2021This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling,...
OBJECTIVES
This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1).
MATERIALS AND METHODS
Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal.
RESULTS
EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007).
CONCLUSION
We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC.
IMPLICATIONS FOR PRACTICE
Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.
Topics: Aged; Anaplastic Lymphoma Kinase; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; China; Female; Gene Rearrangement; Genes, erbB-1; Genes, p53; Genes, ras; Genetic Markers; Genetic Profile; High-Throughput Nucleotide Sequencing; Histone-Lysine N-Methyltransferase; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Lung Neoplasms; Male; Middle Aged; Mutation; Progression-Free Survival; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Retrospective Studies
PubMed: 33655698
DOI: 10.1002/cam4.3649 -
ELife May 2021What level of Ras genes activity leads to the development of cancer?
What level of Ras genes activity leads to the development of cancer?
Topics: Codon; Genes, ras
PubMed: 33998996
DOI: 10.7554/eLife.69192 -
Small GTPases Mar 2020Members of the MYC family of proto-oncogenes are the most commonly deregulated genes in all human cancers. MYC proteins drive an increase in cellular proliferation and... (Review)
Review
Members of the MYC family of proto-oncogenes are the most commonly deregulated genes in all human cancers. MYC proteins drive an increase in cellular proliferation and facilitate multiple aspects of tumor initiation and progression, thereby controlling all hallmarks of cancer. MYC's ability to drive metabolic reprogramming of tumor cells leading to biomass accumulation and cellular proliferation is the most studied function of these oncogenes. MYC also regulates tumor progression and is often implicated in resistance to chemotherapy and in metastasis. While most oncogenic functions of MYC are attributed to its role as a transcription factor, more recently, new roles of MYC as a pro-survival factor in the cytoplasm suggest a previously unappreciated diversity in MYC's roles in cancer progression. This review will focus on the role of MYC in invasion and will discuss the canonical functions of MYC in Epithelial to Mesenchymal Transition and the cytoplasmic functions of MYC-nick in collective migration.
Topics: Animals; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Neoplasm Invasiveness; Neoplasms; Proto-Oncogene Proteins c-myc; Transcription, Genetic
PubMed: 29173017
DOI: 10.1080/21541248.2017.1364821