bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022–05–22
six papers selected by
Sergio Marchini, Humanitas Research
  1. Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer.
  2. Homologous recombination deficiency in diverse cancer types and its correlation with platinum chemotherapy efficiency in ovarian cancer.
  3. Spatially resolved transcriptomics provide a new method for cancer research.
  4. The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination.
  5. Genome-wide methylation profiling of early colorectal cancer using an Illumina Infinium Methylation EPIC BeadChip.
  6. Circular RNAs: Characterization, cellular roles, and applications.
  1. Cancer Drug Resist. 2021 ;4(3): 573-595
    Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer.
    Natasha Rinne, Elizabeth L Christie, Anastasia Ardasheva, Chun Hei Kwok, Nikita Demchenko, Caroline Low, Catherine Tralau-Stewart, Christina Fotopoulou, Paula Cunnea.
      The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials.
    Keywords:  Ovarian cancer; PI3K/AKT/mTOR pathway; chemotherapy resistance; high-grade serous; inhibitors; therapeutics
    DOI:  https://doi.org/10.20517/cdr.2021.05
  2. BMC Cancer. 2022 May 16. 22(1): 550
    Homologous recombination deficiency in diverse cancer types and its correlation with platinum chemotherapy efficiency in ovarian cancer.
    Hao Wen, Zheng Feng, Yutong Ma, Rui Liu, Qiuxiang Ou, Qinhao Guo, Yi Shen, Xue Wu, Yang Shao, Hua Bao, Xiaohua Wu.
       BACKGROUND: Homologous recombination deficiency (HRD) is a molecular biomarker for administrating PARP inhibitor (PARPi) or platinum-based (Pt) chemotherapy. The most well-studied mechanism of causing HRD is pathogenic BRCA1/2 mutations, while HRD phenotype is also present in patients without BRCA1/2 alterations, suggesting other unknown factors.
    METHODS: The targeted next-generation sequencing (GeneseeqPrime® HRD) was used to evaluate the HRD scores of 199 patients (Cohort I). In Cohort II, a total of 85 Pt-chemotherapy-treated high-grade serous ovarian cancer (HGSOC) patients were included for investigating the role of HRD score in predicting treatment efficacy. The concurrent genomic features analyzed along HRD score evaluation were studied in a third cohort with 416 solid tumor patients (Cohort III).
    RESULTS: An HRD score ≥ 38 was predefined as HRD-positive by analyzing Cohort I (range: 0-107). Over 95% of the BRCA1/2-deficient cases of Cohort I were HRD-positive under this threshold. In Cohort II, Pt-sensitive patients have significantly higher HRD scores than Pt-resistant patients (median: 54 vs. 34, p = 0.031) and a significantly longer PFS was observed in HRD-positive patients (median: 548 vs. 343 days, p = 0.003). Furthermore, TP53, NCOR1, and PTK2 alterations were enriched in HRD-positive patients. In Cohort III, impaired homologous recombination repair pathway was more frequently observed in HRD-positive patients without BRCA1/2 pathogenic mutations. The alteration enrichment of TP53, NCOR1, and PTK2 observed in Cohort II was also validated by the ovarian subgroup in Cohort III.
    CONCLUSIONS: Using an in-house HRD evaluation method, our findings show that overall HRR gene mutations account for a significant part of HRD in the absence of BRCA1/2 aberrations, and suggest that HRD positive status might be a predictive biomarker of Pt-chemotherapy.
    Keywords:  BRCA1/2; Homologous recombination deficiency; NGS; Platinum chemotherapy
    DOI:  https://doi.org/10.1186/s12885-022-09602-4
  3. J Exp Clin Cancer Res. 2022 May 19. 41(1): 179
    Spatially resolved transcriptomics provide a new method for cancer research.
    Bowen Zheng, Lin Fang.
      A major feature of cancer is the heterogeneity, both intratumoral and intertumoral. Traditional single-cell techniques have given us a comprehensive understanding of the biological characteristics of individual tumor cells, but the lack of spatial context of the transcriptome has limited the study of cell-to-cell interaction patterns and hindered further exploration of tumor heterogeneity. In recent years, the advent of spatially resolved transcriptomics (SRT) technology has made possible the multidimensional analysis of the tumor microenvironment in the context of intact tissues. Different SRT methods are applicable to different working ranges due to different working principles. In this paper, we review the advantages and disadvantages of various current SRT methods and the overall idea of applying these techniques to oncology studies, hoping to help researchers find breakthroughs. Finally, we discussed the future direction of SRT technology, and deeper investigation into the complex mechanisms of tumor development from different perspectives through multi-omics fusion, paving the way for precisely targeted tumor therapy.
    Keywords:  Cancer; Research Progress; Spatially resolved transcriptomics
    DOI:  https://doi.org/10.1186/s13046-022-02385-3
  4. Front Endocrinol (Lausanne). 2022 ;13 886533
    The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination.
    Sabrina J Ritch, Carlos M Telleria.
      Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.
    Keywords:  ascites fluid; fallopian tube epithelium; high-grade serous ovarian cancer (HGSOC); omental metastasis; ovarian surface epithelium; peritoneal carcinomatosis; transcoelomic dissemination
    DOI:  https://doi.org/10.3389/fendo.2022.886533
  5. World J Gastrointest Oncol. 2022 Apr 15. 14(4): 935-946
    Genome-wide methylation profiling of early colorectal cancer using an Illumina Infinium Methylation EPIC BeadChip.
    Yu-Ling Wu, Tao Jiang, Wei Huang, Xing-Yu Wu, Peng-Jun Zhang, Ya-Ping Tian.
       BACKGROUND: DNA methylation is a part of epigenetic modification, that is closely related to the growth and development of colorectal cancer (CRC). Specific methylated genes and methylated diagnostic models of tumors have become current research focuses. The methylation status of circulating DNA in plasma might serve as a potential biomarker for CRC.
    AIM: To investigate genome-wide methylation pattern in early CRC using the Illumina Infinium Human Methylation 850K BeadChip.
    METHODS: The 850K Methylation BeadChip was used to analyze the genome-wide methylation status of early CRC patients (n = 5) and colorectal adenoma patients (n = 5). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were performed on the selected differentially methylated sites to further discover candidate methylation biomarkers in plasma.
    RESULTS: A total of 1865 methylated CpG sites with significant differences were detected, including 676 hypermethylated sites and 1189 hypomethylated sites. The distribution of these sites covered from the 1st to 22nd chromosomes and are mainly distributed on the gene body and gene promoter region. GO and KEGG enrichment analysis showed that the functions of these genes were related to biological regulation, molecular binding, transcription factor activity and signal transduction pathway.
    CONCLUSION: The study demonstrated that the Illumina Infinium Human Methylation 850K BeadChip can be used to investigate genome-wide methylation status of plasma DNA in early CRC and colorectal adenoma patients.
    Keywords:  850K Methylation BeadChip; Colorectal cancer; DNA methylation; Plasma; colorectal adenoma
    DOI:  https://doi.org/10.4251/wjgo.v14.i4.935
  6. Cell. 2022 May 13. pii: S0092-8674(22)00468-8. [Epub ahead of print]
    Circular RNAs: Characterization, cellular roles, and applications.
    Chu-Xiao Liu, Ling-Ling Chen.
      Most circular RNAs are produced from the back-splicing of exons of precursor mRNAs. Recent technological advances have in part overcome problems with their circular conformation and sequence overlap with linear cognate mRNAs, allowing a better understanding of their cellular roles. Depending on their localization and specific interactions with DNA, RNA, and proteins, circular RNAs can modulate transcription and splicing, regulate stability and translation of cytoplasmic mRNAs, interfere with signaling pathways, and serve as templates for translation in different biological and pathophysiological contexts. Emerging applications of RNA circles to interfere with cellular processes, modulate immune responses, and direct translation into proteins shed new light on biomedical research. In this review, we discuss approaches used in circular RNA studies and the current understanding of their regulatory roles and potential applications.
    Keywords:  RBP; RNA circle; RNA-binding protein; aptamer; back-splicing; circRNA; circular RNA application; circular RNA modality; circular RNA therapeutics; circular RNA translation; immunogenicity
    DOI:  https://doi.org/10.1016/j.cell.2022.04.021
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