bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024‒06‒16
thirteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Direct inhibition of the YAP:TEAD interaction: an unprecedented drug discovery challenge.
  2. The phosphoinositide PI5P inhibits the Hippo pathway effector YAP.
  3. Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors.
  4. Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.
  5. A war on many fronts: cross disciplinary approaches for novel cancer treatment strategies.
  6. Computational identification of surface markers for isolating distinct subpopulations from heterogeneous cancer cell populations.
  7. Developing a dormancy-associated ECM signature in TNBC that is linked to immunosuppressive tumor microenvironment and selective sensitivity to MAPK inhibitors.
  8. DNA damage causes ATM-dependent heterochromatin loss leading to nuclear softening, blebbing, and rupture.
  9. Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis.
  10. Pleomorphism in Biological Units of Life: Morphological Heterogeneity in Cells Does Not Translate Uniformly to Subcellular Components.
  11. Aptamer-Drug conjugates for a targeted and synergistic anticancer Response: Exploiting T30923-5-fluoro-2'-deoxyuridine (INT-FdU) derivatives.
  12. Privileged proteins with a second residence: dual targeting and conditional re-routing of mitochondrial proteins.
  13. FDA approves first telomerase inhibitor.
  1. ChemMedChem. 2024 Jun 11. e202400361
    Direct inhibition of the YAP:TEAD interaction: an unprecedented drug discovery challenge.
    Patrick Chene.
      The Hippo pathway, which is key in organ morphogenesis, is frequently deregulated in cancer. The TEAD (TEA domain family member) transcription factors are the most distal elements of this pathway, and their activity is regulated by proteins such as YAP (Yes-associated protein). The identification of inhibitors of the YAP:TEAD interaction is one approach to develop novel anticancer drugs: the first clinical candidate (IAG933) preventing the association between these two proteins by direct competition has just been reported. The discovery of this molecule was particularly challenging because the interface between these two proteins is large (~ 3500 Å2 buried in complex formation) and made up of distinct contact areas. The most critical of these involves an omega-loop (Ω-loop), a secondary structure element rarely found in protein-protein interactions. This review summarizes how the knowledge gained from structure-function studies of the interaction between the Ω-loop of YAP and TEAD was used to devise the strategy to identify potent low-molecular weight compounds that show a pronounced anti-tumor effect.
    Keywords:  Drug discovery; Hippo pathway; TEAD; YAP; protein-protein interactions
    DOI:  https://doi.org/10.1002/cmdc.202400361
  2. Nat Rev Mol Cell Biol. 2024 Jun 10.
    The phosphoinositide PI5P inhibits the Hippo pathway effector YAP.
    Kim Baumann.
      
    DOI:  https://doi.org/10.1038/s41580-024-00750-y
  3. bioRxiv. 2024 May 28. pii: 2024.05.23.592075. [Epub ahead of print]
    Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors.
    Chuwei Lin, Catherine Sniezek, Ross M Giglio, Rashmi Karki, Christopher McGann, Benjamin A Garcia, Jose L McFaline-Figeroa, Devin K Schweppe.
      Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogenous and dependent on factors such as the genetic background, metabolic state, and on-/off-target engagement of individual small-molecule drugs. To determine the mechanisms that drive these heterogeneous cellular responses, we quantified chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitor (HDACi) -treated cells derived from diverse genetic backgrounds. We utilized high-throughput sample multiplexed proteomics and integrated intelligent data acquisition methods to map proteomes of cancer cell lines in response to HDACi. We determined cell type-specific and ubiquitous cellular responses based on the quantification of 10,621 total proteins. We then established how coordinated remodeling of the proteome, transcriptome and chromatin state of HDACi treated cancer cells revealed convergent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) molecular phenotypes. HDACi-regulated proteins differ greatly across cell lines owing to heterogeneous molecular states of these cell lines. Finally, we demonstrated that HDACi treatment drove a highly cell-type specific response that may in part be explained by cell line-specific off-target drug engagement.
    DOI:  https://doi.org/10.1101/2024.05.23.592075
  4. Mol Cancer. 2024 Jun 10. 23(1): 121
    Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.
    Rashmi Bharti, Goutam Dey, Debjit Khan, Alex Myers, Olivia G Huffman, Caner Saygin, Chad Braley, Elliott Richards, Naseer Sangwan, Belinda Willard, Justin D Lathia, Paul L Fox, Feng Lin, Babal Kant Jha, J Mark Brown, Jennifer S Yu, Mohammed Dwidar, Amy Joehlin-Price, Roberto Vargas, Chad M Michener, Michelle S Longworth, Ofer Reizes.
      BACKGROUND: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers.METHODS: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing.
    RESULTS: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2.
    CONCLUSIONS: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.
    DOI:  https://doi.org/10.1186/s12943-024-02028-5
  5. Front Genet. 2024 ;15 1383676
    A war on many fronts: cross disciplinary approaches for novel cancer treatment strategies.
    Adriana Del Pino Herrera, Meghan C Ferrall-Fairbanks.
      Cancer is a disease characterized by uncontrolled cellular growth where cancer cells take advantage of surrounding cellular populations to obtain resources and promote invasion. Carcinomas are the most common type of cancer accounting for almost 90% of cancer cases. One of the major subtypes of carcinomas are adenocarcinomas, which originate from glandular cells that line certain internal organs. Cancers such as breast, prostate, lung, pancreas, colon, esophageal, kidney are often adenocarcinomas. Current treatment strategies include surgery, chemotherapy, radiation, targeted therapy, and more recently immunotherapy. However, patients with adenocarcinomas often develop resistance or recur after the first line of treatment. Understanding how networks of tumor cells interact with each other and the tumor microenvironment is crucial to avoid recurrence, resistance, and high-dose therapy toxicities. In this review, we explore how mathematical modeling tools from different disciplines can aid in the development of effective and personalized cancer treatment strategies. Here, we describe how concepts from the disciplines of ecology and evolution, economics, and control engineering have been applied to mathematically model cancer dynamics and enhance treatment strategies.
    Keywords:  cancer; control theory; ecology; economics; engineering; evolution; mathematical modeling
    DOI:  https://doi.org/10.3389/fgene.2024.1383676
  6. bioRxiv. 2024 Jun 02. pii: 2024.05.28.596337. [Epub ahead of print]
    Computational identification of surface markers for isolating distinct subpopulations from heterogeneous cancer cell populations.
    Andrea L Gardner, Tyler A Jost, Amy Brock.
      Intratumor heterogeneity reduces treatment efficacy and complicates our understanding of tumor progression. There is a pressing need to understand the functions of heterogeneous tumor cell subpopulations within a tumor, yet biological systems to study these processes in vitro are limited. With the advent of single-cell RNA sequencing (scRNA-seq), it has become clear that some cancer cell line models include distinct subpopulations. Heterogeneous cell lines offer a unique opportunity to study the dynamics and evolution of genetically similar cancer cell subpopulations in controlled experimental settings. Here, we present clusterCleaver, a computational package that uses metrics of statistical distance to identify candidate surface markers maximally unique to transcriptomic subpopulations in scRNA-seq which may be used for FACS isolation. clusterCleaver was experimentally validated using the MDA-MB-231 and MDA-MB-436 breast cancer cell lines. ESAM and BST2/tetherin were experimentally confirmed as surface markers which identify and separate major transcriptomic subpopulations within MDA-MB-231 and MDA-MB-436 cells, respectively. clusterCleaver is a computationally efficient and experimentally validated workflow for identification and enrichment of distinct subpopulations within cell lines which paves the way for studies on the coexistence of cancer cell subpopulations in well-defined in vitro systems.
    DOI:  https://doi.org/10.1101/2024.05.28.596337
  7. Heliyon. 2024 Jun 15. 10(11): e32106
    Developing a dormancy-associated ECM signature in TNBC that is linked to immunosuppressive tumor microenvironment and selective sensitivity to MAPK inhibitors.
    Yang Dong, Jin Bai, Jianjun Zhou.
      Aims: Cellular dormancy is a state of quiescence subpopulation of tumor cells, characterized by low differentiation and lack of mitotic activity. They could evade chemotherapy and targeted therapy, leading to drug resistance and disease recurrence. Recent studies have shown a correlation between dormant cancer cells and unique extracellular matrix (ECM) composition, which is critical in regulating cell behavior. However, their interacting roles in TNBC patients remains to be characterized.Main methods: Dormant cancer cells in MDA-MB-231 cell line with highest PKH26 dye-retaining were FACS-sorted and gene expression was then analyzed. Dormant associated ECM (DA-ECM) signature was characterized by pathway analysis. Unsupervised hierarchical clustering was used to define distinct ECM features for TNBC patients. ECM-specific tumor biology was defined by integration of bulk RNA-seq with single-cell RNA-seq data, analysis of ligand-receptor interactions and enriched biological pathways, and in silico drug screening. We validated the sensitivity of dormant cancer cells to MAPK inhibitors by flow cytometry in vitro.
    Key findings: We observed that dormant TNBC cells preferentially expressed ∼10 % DA-ECM genes. The DA-ECM High subtype defined by unsupervised hierarchical clustering analysis was associated with immunosuppressive tumor microenvironment. Moreover, ligand-receptor interaction and pathway analysis revealed that the DA-ECM High subtype may likely help maintain tumor cell dormancy through MAPK, Hedgehog and Notch signaling pathways. Finally, in silico drug screening against the DA-ECM signature and in vitro assay showed dormant cancer cells were relatively sensitive to the MAPK pathway inhibitors, which may represent a potential therapeutic strategy for treating TNBC.
    Significance: Collectively, our research revealed that dormancy-associated ECM characterized tumor cells possess significant ECM remodeling capacity, and treatment strategies towards these cells could improve TNBC patient outcome.
    Keywords:  Cellular dormancy; Chemoresistance; Extracellular matrix; MAPK signaling pathway; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e32106
  8. bioRxiv. 2024 May 29. pii: 2024.05.24.595790. [Epub ahead of print]
    DNA damage causes ATM-dependent heterochromatin loss leading to nuclear softening, blebbing, and rupture.
    Nebiyat Eskndir, Manseeb Hossain, Marilena L Currey, Mai Pho, Yasmin Berrada, Andrew D Stephens.
      The nucleus must maintain stiffness to protect the shape and integrity of the nucleus to ensure proper function. Defects in nuclear stiffness caused from chromatin and lamin perturbations produce abnormal nuclear shapes common in aging, heart disease, and cancer. Loss of nuclear shape via protrusions called blebs leads to nuclear rupture that is well-established to cause nuclear dysfunction, including DNA damage. However, it remains unknown how increased DNA damage affects nuclear stiffness, shape, and ruptures, which could create a negative feedback loop. To determine if increased DNA damage alters nuclear physical properties, we treated MEF cells with DNA damage drugs cisplatin and bleomycin. DNA damage drugs caused increased nuclear blebbing and rupture in interphase nuclei within a few hours and independent of mitosis. Micromanipulation force measurements reveal that DNA damage decreased chromatin-based nuclear mechanics but did not change lamin-based strain stiffening at long extensions relative to wild type. Immunofluorescence measurements of DNA damage treatments reveal the mechanism is an ATM-dependent decrease in heterochromatin leading to nuclear weaken, blebbing, and rupture which can be rescued upon ATM inhibition treatment. Thus, DNA damage drugs cause ATM-dependent heterochromatin loss resulting in nuclear softening, blebbing, and rupture.
    DOI:  https://doi.org/10.1101/2024.05.24.595790
  9. Cancer Res. 2024 Jun 11.
    Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis.
    Yinyin Shu, Xiaoni Jin, Mintao Ji, Zhisen Zhang, Xiuxiu Wang, Haisheng Liang, Shuangshuang Lu, Shuai Dong, Yiping Lin, Yuhan Guo, Qiuyu Zhuang, Yuhong Wang, Zhe Lei, Lingchuan Guo, Xuanyu Meng, Guangming Zhou, Wensheng Zhang, Lei Chang.
      YAP is a central player in cancer development with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/TAZ and the DNA damage response. Here, we investigated the mechanistic underpinnings of the crosstalk between DNA damage repair and YAP activity. Ku70, a key component of the non-homologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP. Depletion of Ku70 enhanced interaction between YAP and TEAD4 and boosted YAP transcriptional capacity. Consequently, Ku70 loss enhanced tumorigenesis in colon cancer and hepatocellular carcinoma (HCC) in vivo. YAP impeded DNA damage repair and elevated genome instability by inducing PARP1 degradation through the SMURF2-mediated ubiquitin-proteasome pathway. Analysis of HCC patient samples substantiated the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability. In conclusion, this research provides insight into the mechanistic interactions between YAP and key regulators of DNA damage repair, highlighting the role of a Ku70-YAP-PARP1 axis in preserving genome stability.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-4034
  10. ACS Omega. 2024 Jun 04. 9(22): 23377-23389
    Pleomorphism in Biological Units of Life: Morphological Heterogeneity in Cells Does Not Translate Uniformly to Subcellular Components.
    Pragya Singh, Aditya Mittal.
      The interplay of the three-dimensional (3D) distribution of various subcellular components and their interactions are expected to control overall cellular morphology in biology. In this study, we aimed to determine whether the pleomorphy observed at the whole-cell level is being reflected by the components constituting the cells by focusing on the 3D distribution of pixel intensities at the single-cell level of the whole (cell) and its parts (the seven subcellular components of the cells-self-assemblies of smaller units). We rigorously acquired and analyzed the image data of RAW264.7 cells at the single-cell level. We report asymmetries in the spatial distribution of pixel intensities at the whole-cell and subcellular component levels along with the occurrence of alterations when pleomorphism is reduced by synchronization of the cell cycle. From our repertoire of seven subcellular components, we report ER, mitochondria, and tubulin to be independent of whole-cell apico-basal heterogeneity of optical density while nuclear, plasma membrane, lysosomal, and actin fluorescence distributions are found to contribute to the apico-basal polarity of the whole cell. While doing so, we have also developed an image analysis algorithm utilizing 2D segmentation to analyze the single cells in 3D using confocal microscopy, a technique that allows us to analyze cellular states in their native hydrated state.
    DOI:  https://doi.org/10.1021/acsomega.3c10062
  11. Eur J Pharm Biopharm. 2024 Jun 07. pii: S0939-6411(24)00180-2. [Epub ahead of print] 114354
    Aptamer-Drug conjugates for a targeted and synergistic anticancer Response: Exploiting T30923-5-fluoro-2'-deoxyuridine (INT-FdU) derivatives.
    Daniela Benigno, Natalia Navarro, Anna Aviñó, Veronica Esposito, Aldo Galeone, Antonella Virgilio, Carme Fàbrega, Ramon Eritja.
      One of the most appealing approaches for cancer treatment is targeted therapy, which is based on the use of drugs able to target cancer cells without affecting normal ones. This strategy lets to overcome the major limitation of conventional chemotherapy, namely the lack of specificity of anticancer drugs, which often leads to severe side effects, decreasing the therapy effectiveness. Delivery of cell-killing substances to tumor cells is one-way targeted drug therapy can work. Generally, monoclonal antibodies are combined with chemotherapeutic drugs, allowing cellular uptake through the binding to their targets on the surface of cancer cells. Aptamer-drug conjugates represent a promising alternative solution to antibodies to minimize off-target effects, considering the remarkable selective binding capabilities of aptamers. In this study, to enhance the therapeutic efficacy of the antineoplastic agent 5-fluoro-2'-deoxyuridine (FdU) in various cancer cells, we focused on the development of a novel conjugate using the antiproliferative aptamer T30923 (INT) as a drug vehicle. Three derivatives composed of T30923 conjugated with a different number of FdU units were synthesized, and their structural and biological properties were thoroughly characterized, highlighting their potential for targeted and synergistic anticancer responses.
    Keywords:  5-fluoro-2′-deoxyuridine; Aptamer-drug; Cancer therapy; G-quadruplex; T30923 aptamer
    DOI:  https://doi.org/10.1016/j.ejpb.2024.114354
  12. FEBS J. 2024 Jun 10.
    Privileged proteins with a second residence: dual targeting and conditional re-routing of mitochondrial proteins.
    Ophry Pines, Margalit Horwitz, Johannes M Herrmann.
      Almost all mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol as precursor proteins. Signals in the amino acid sequence of these precursors ensure their targeting and translocation into mitochondria. However, in many cases, only a certain fraction of a specific protein is transported into mitochondria, while the rest either remains in the cytosol or undergoes reverse translocation to the cytosol, and can populate other cellular compartments. This phenomenon is called dual localization which can be instigated by different mechanisms. These include alternative start or stop codons, differential transcripts, and ambiguous or competing targeting sequences. In many cases, dual localization might serve as an economic strategy to reduce the number of required genes; for example, when the same groups of enzymes are required both in mitochondria and chloroplasts or both in mitochondria and the nucleus/cytoplasm. Such cases frequently employ ambiguous targeting sequences to distribute proteins between both organelles. However, alternative localizations can also be used for signaling, for example when non-imported precursors serve as mitophagy signals or when they represent transcription factors in the nucleus to induce the mitochondrial unfolded stress response. This review provides an overview regarding the mechanisms and the physiological consequences of dual targeting.
    Keywords:  dual targeting; mitochondria; protein import; start codon; targeting signals
    DOI:  https://doi.org/10.1111/febs.17191
  13. Nat Rev Drug Discov. 2024 Jun 14.
    FDA approves first telomerase inhibitor.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-024-00102-7
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