bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒07‒23
nine papers selected by
Ankita Daiya
BITS Pilani

  1. MedComm (2020). 2023 Aug;4(4): e317
      Although great advances have been made over the past decades, therapeutics for osteosarcoma are quite limited. We performed long-read RNA sequencing and tandem mass tag (TMT)-based quantitative proteome on osteosarcoma and the adjacent normal tissues, next-generation sequencing (NGS) on paired osteosarcoma samples before and after neoadjuvant chemotherapy (NACT), and high-throughput drug combination screen on osteosarcoma cell lines. Single-cell RNA sequencing data were analyzed to reveal the heterogeneity of potential therapeutic target genes. Additionally, we clarified the synergistic mechanisms of doxorubicin (DOX) and HDACs inhibitors for osteosarcoma treatment. Consequently, we identified 2535 osteosarcoma-specific genes and several alternative splicing (AS) events with osteosarcoma specificity and/or patient heterogeneity. Hundreds of potential therapeutic targets were identified among them, which showed the core regulatory roles in osteosarcoma. We also identified 215 inhibitory drugs and 236 synergistic drug combinations for osteosarcoma treatment. More interestingly, the multiomic analysis pointed out the pivotal role of HDAC1 and TOP2A in osteosarcoma. HDAC inhibitors synergized with DOX to suppress osteosarcoma both in vitro and in vivo. Mechanistically, HDAC inhibitors synergized with DOX by downregulating SP1 to transcriptionally modulate TOP2A expression. This study provided a comprehensive view of molecular features, therapeutic targets, and synergistic drug combinations for osteosarcoma.
    Keywords:  drug combination; high‐throughput screen; multiomic analysis; osteosarcoma; therapeutic target
  2. bioRxiv. 2023 Jul 03. pii: 2023.07.02.547443. [Epub ahead of print]
      APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of ΔNp63 in gefitinib-resistant cells reduces the expression of the p63 target genes IL1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.
  3. Front Oncol. 2023 ;13 1213426
      Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = 165, 73%) were studied. One hundred forty-nine invasive tumors contained adjacent preinvasive tissue, bringing the total number of preinvasive lesions examined to 211 (62 + 149). There was adjacent benign squamous epithelium in 50.2% (114/227) of OSSN samples. Nuclear YAP- 1 was significantly overexpressed in preinvasive (Fisher's (F): p <.0001, Monte Carlo (MC): p <.0001) and invasive (F: p <.0001, MC: p <.0001) OSSN in comparison to adjacent benign squamous epithelium when analyzed for basal keratinocyte positive count, staining intensity, expression pattern, and Immunostaining intensity-distribution index. YAP-1 expression did not differ between preinvasive and invasive OSSN (p >.05), keratinizing and non- keratinizing cancer (p >.05), or between T1/T2 and T3/T4 stages in invasive tumors (p >.05). However, grade 2 and 3 tumors had significantly stronger nucleus YAP-1 overexpression intensity than grade 1 tumors (F: p = .0078, MC: p = .0489). By immunohistochemistry, we identified significant overexpression (upregulation of YAP-1 protein expression) in preinvasive and invasive OSSN lesions compared to neighboring benign squamous epithelium. YAP-1 expression was significantly higher in poorly and moderately differentiated invasive squamous cancer than in well-differentiated carcinomas. Overexpression of YAP-1 within the margin of preinvasive and invasive OSSN, but not in the neighboring normal epithelium, indicates that it plays a role in the development and progression of OSSN.
    Keywords:  Zambia; invasive OSSN; ocular surface squamous neoplasia (OSSN); preinvasive OSSN; yes-associated protein-1 (YAP-1)
  4. Natl Sci Rev. 2023 Aug;10(8): nwad165
      Biophysical cues of the cellular microenvironment tremendously influence cell behavior by mechanotransduction. However, it is still unclear how cells sense and transduce the mechanical signals from 3D geometry to regulate cell function. Here, the mechanotransduction of human mesenchymal stem cells (MSCs) triggered by 3D micropatterns and its effect on the paracrine of MSCs are systematically investigated. Our findings show that 3D micropattern force could influence the spatial reorganization of the cytoskeleton, leading to different local forces which mediate nucleus alteration such as orientation, morphology, expression of Lamin A/C and chromatin condensation. Specifically, in the triangular prism and cuboid micropatterns, the ordered F-actin fibers are distributed over and fully transmit compressive forces to the nucleus, which results in nuclear flattening and stretching of nuclear pores, thus enhancing the nuclear import of YES-associated protein (YAP). Furthermore, the activation of YAP significantly enhances the paracrine of MSCs and upregulates the secretion of angiogenic growth factors. In contrast, the fewer compressive forces on the nucleus in cylinder and cube micropatterns cause less YAP entering the nucleus. The skin repair experiment provides the first in vivo evidence that enhanced MSCs paracrine by 3D geometry significantly promotes tissue regeneration. The current study contributes to understanding the in-depth mechanisms of mechanical signals affecting cell function and provides inspiration for innovative design of biomaterials.
    Keywords:  3D micropattern force; bioactive materials; mechanotransduction; paracrine; tissue regeneration
  5. Int Immunopharmacol. 2023 Jul 18. pii: S1567-5769(23)00986-4. [Epub ahead of print]122 110661
      Histone deacetylases (HDACs) play a crucial role in the epigenetic regulation of gene expression by remodelling chromatin. Isoenzymes of the HDAC family exhibit aberrant regulation in a wide variety of cancers as well as several inflammatory lung disorders like chronic obstructive pulmonary disease (COPD). Inhibition of HDACs is a potential therapeutic strategy that could be used to reverse epigenetic modification. Trichostatin A (TSA), a powerful histone deacetylase (HDAC) inhibitor, has anti-cancer effects in numerous cancer types. However, it is not yet apparent how HDAC inhibitors affect human non-small cell lung cancer cells (NSCLC) and COPD. This study aims to investigate TSA's role in restoring mitochondrial dysfunction and its effect on hypoxia and inflammation in CD4+T cells obtained from patients with COPD and lung cancer. As a result of treatment with TSA, there is a reduction in the expression of inflammatory cytokines and a decreased enrichment of transcriptional factors associated with inflammation at VEGFA gene loci. We have seen a substantial decrease in the expression of NF-κB and HIF1α, which are the critical mediators of inflammation and hypoxia, respectively. Following TSA treatment, mtTFA expression was increased, facilitating patients with COPD and NSCLC in the recovery of their dysfunctional mitochondria. Furthermore, we have discovered that TSA treatment in patients with COPD and NSCLC may lead to immunoprotective ness by inducing Th1ness. Our finding gives a new insight into the existing body of knowledge regarding TSA-based therapeutic methods and highlights the necessity of epigenetic therapy for these devastating lung disorders.
    Keywords:  Chronic Obstructive Pulmonary Disease (COPD); Histone deacetylases Inhibitor; Inflammation; Mitochondrial dysfunction; Non-Small Cell Lung Cancer (NSCLC)
  6. Nature. 2023 Jul 19.
      Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
  7. Proteomics. 2023 Jul 20. e2200243
      Cellular communication relies on signaling circuits whose statuses are mainly modulated by soluble biomolecules such as carbohydrates, lipids, proteins, and metabolites as well as extracellular vesicles (EVs). Therefore, the active secretion of such biomolecules is critical for both cell homeostasis and proper pathophysiological responses in a timely fashion. In this context, proteins are among the main modulators of such biological responses. Hence, profiling cell line secretomes may be an opportunity for the identification of "signatures" of specific cell types (i.e., stromal or metastatic cells) with important prognostic/therapeutic value. This review will focus on the biological implications of cell secretomes in the context of cancer, as well as their functional roles in shaping the tumoral microenvironment (TME) and communication status of participating cells.
    Keywords:  animal proteomics; biology; biomarkers; biomedicine; body fluids; cancer; cell; cell biology; secretome
  8. Antioxid Redox Signal. 2023 Jul 20.
      Mitochondria are subcellular organelles performing essential metabolic functions contributing to cellular bioenergetics and regulation of cell growth or death. The basic mitochondrial function in fulfilling the need for cell growth and vitality is evidenced by the conditional state whereby cancer cells with depleted mitochondrial DNA (rho zero cells) are no longer capable of forming tumors until newly recruited mitochondria are internalized into the rho zero cells. Herein lies the absolute dependency on mitochondria for tumor growth. In addition, mitochondria are key regulators of cell death (by apoptosis, necroptosis, or other forms of cell death) and are therefore important targets for anticancer therapy. Mitochondrial plasticity regulating their state of fusion or fission is also key to the chemoresistance properties of cancer cells by promoting pro-survival pathways enabling the mitochondria to mitigate against the cellular stresses and extreme conditions within the tumor microenvironment caused by chemotherapy, hypoxia, or oxidative stress. This review discusses many characteristics of mitochondria, the processes and pathways controlling the dynamic changes occurring in the morphology of mitochondria, the roles of reactive oxygen species, and their relationship with mitochondrial fission or fusion. It also examines the relationship of redox to mitophagy when mitochondria become compromised and its effect on cancer cell survival, stemness and the changes accompanying malignant progression from primary tumors to metastatic disease. A challenging question that arises is whether the changes in mitochondrial dynamics and their regulation can provide opportunities for improving drug targeting during cancer treatment and enhancing survival outcomes.
  9. STAR Protoc. 2023 Jul 14. pii: S2666-1667(23)00414-8. [Epub ahead of print]4(3): 102447
      Here, we present a protocol for spatially annotated single-cell sequencing, a technique for spatially profiling intratumor heterogeneity with deep single-cell RNA sequencing and single-cell resolution. By combining live-cell imaging and photopatterned illumination, we describe steps to identify regions of interest in an in vitro tumor model, label the selected cells with photoactivatable dyes, and isolate and subject them to scRNAseq. This protocol can be applied to a range of cell lines and could be expanded to tissue sections. For complete details on the use and execution of this protocol, please refer to Smit et al. (2022).1.
    Keywords:  Bioinformatics; Cancer; Microscopy; RNAseq