bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒12‒25
ten papers selected by
Ankita Daiya
BITS Pilani
  1. Single cell analysis reveals transcriptomic features of drug tolerant persisters and stromal adaptation in a patient-derived EGFR-mutated lung adenocarcinoma xenograft model.
  2. Single-cell nanobody-based profiles of multiple epigenetic modalities and chromatin velocity.
  3. Small-Molecule Cyanamide Pan-TEAD·YAP1 Covalent Antagonists.
  4. DNA barcoding and gene expression recording reveal the presence of cancer cells with unique properties during tumor progression.
  5. Blockage of Nrf2 and autophagy by L-selenocystine induces selective death in Nrf2-addicted colorectal cancer cells through p62-Keap-1-Nrf2 axis.
  6. Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma.
  7. YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches.
  8. Bio-Mechanical Model of Osteosarcoma Tumor Microenvironment: A Porous Media Approach.
  9. A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations.
  10. Metabolic switch in cancer - Survival of the fittest.
  1. J Thorac Oncol. 2022 Dec 16. pii: S1556-0864(22)01964-5. [Epub ahead of print]
    Single cell analysis reveals transcriptomic features of drug tolerant persisters and stromal adaptation in a patient-derived EGFR-mutated lung adenocarcinoma xenograft model.
    Nadeem Moghal, Quan Li, Erin L Stewart, Masashi Mikubo, Roya Navab, Elisa D'Arcangelo, Sebastiao Martins-Filho, Vibha Raghavan, Nhu-An Pham, Ming Li, Frances A Shepherd, Geoffrey Liu, Ming-Sound Tsao.
      INTRODUCTION: Targeted therapies require life-long treatment, as drug discontinuation invariably leads to tumor recurrence. Recurrence is mainly driven by minor subpopulations of drug tolerant persister (DTP) cells that survive the cytotoxic drug effect. In lung cancer, DTP studies have mainly been conducted with cell line models.METHODS: We conducted an in vivo DTP study using a lung adenocarcinoma (LUAD) patient-derived xenograft (PDX) tumor driven by an epidermal growth factor receptor (EGFR) mutation. Daily treatment of tumor-bearing mice for 5-6 weeks with the EGFR inhibitor erlotinib markedly shrunk tumors and generated DTPs, which were analyzed by whole exome, bulk population transcriptome, and single cell RNA sequencing (scRNA-seq).
    RESULTS: DTP tumors maintained the genomic clonal architecture of untreated baseline (BL) tumors, but showed reduced proliferation. scRNA-seq identified a rare (∼4%) subpopulation of BL cells (DTP-like, DTPL) with transcriptomic similarity to DTP cells and intermediate activity of pathways that are upregulated in DTPs. Furthermore, the predominant TGF-β activated cancer-associated fibroblast (CAF) population in BL tumors was replaced by a CAF population enriched for IL6 production. In vitro experiments indicate that these populations interconvert depending on the levels of TGF-β versus NF-κB signaling, which is modulated by TKI presence. DTPs showed signs of increased NF-κB and STAT3 signaling, which may promote their survival.
    CONCLUSION: DTPs may arise from a specific pre-existing subpopulation of cancer cells with partial activation of specific drug resistance pathways. TKI treatment induces DTPs showing greater activation of these pathways while converting the major pre-existing CAF population into a new state that may further promote DTP survival.
    Keywords:  cancer-associated fibroblasts; drug tolerance; erlotinib; persisters; resistance; sensitizing mutation; stroma
    DOI:  https://doi.org/10.1016/j.jtho.2022.12.003
  2. Nat Biotechnol. 2022 Dec 19.
    Single-cell nanobody-based profiles of multiple epigenetic modalities and chromatin velocity.
      
    DOI:  https://doi.org/10.1038/s41587-022-01596-5
  3. J Med Chem. 2022 Dec 23.
    Small-Molecule Cyanamide Pan-TEAD·YAP1 Covalent Antagonists.
    Khuchtumur Bum-Erdene, I-Ju Yeh, Giovanni Gonzalez-Gutierrez, Mona K Ghozayel, Karen Pollok, Samy O Meroueh.
      Transcriptional enhanced associate domains (TEADs) are transcription factors that bind to cotranscriptional activators like the yes-associated protein (YAP) or its paralog transcriptional coactivator with a PDZ-binding motif (TAZ). TEAD·YAP/TAZ target genes are involved in tissue and immune homeostasis, organ size control, tumor growth, and metastasis. Here, we report isoindoline and octahydroisoindole small molecules with a cyanamide electrophile that forms a covalent bond with a conserved cysteine in the TEAD palmitate-binding cavity. Time- and concentration-dependent studies against TEAD1-4 yielded second-order rate constants kinact/KI greater than 100 M-1 s-1. Compounds inhibited YAP1 binding to TEADs with submicromolar IC50 values. Cocrystal structures with TEAD2 enabled structure-activity relationship studies. In mammalian cells, compounds suppressed CTGF mRNA levels and inhibited TEAD1-4 transcriptional activity with submicromolar IC50 values. Inhibition of TEAD binding to YAP1 in mammalian cells was also observed. Several compounds inhibited the cell viability of sarcoma, hepatocellular carcinoma, glioblastoma, and breast cancer cells with single-digit micromolar IC50 values.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01189
  4. Cell Mol Life Sci. 2022 Dec 23. 80(1): 17
    DNA barcoding and gene expression recording reveal the presence of cancer cells with unique properties during tumor progression.
    Yuka Umeki, Noriaki Ogawa, Yuko Uegaki, Kotaro Saga, Yasufumi Kaneda, Keisuke Nimura.
      Tumors comprise diverse cancer cell populations with specific capabilities for adaptation to the tumor microenvironment, resistance to anticancer treatments, and metastatic dissemination. However, whether these populations are pre-existing in cancer cells or stochastically appear during tumor growth remains unclear. Here, we show the heterogeneous behaviors of cancer cells regarding response to anticancer drug treatments, formation of lung metastases, and expression of transcription factors related to cancer stem-like cells using a DNA barcoding and gene expression recording system. B16F10 cells maintained clonal diversity after treatment with HVJ-E, a UV-irradiated Sendai virus, and the anticancer drug dacarbazine. PBS treatment of the primary tumor and intravenous injection of B16F10 cells resulted in metastases formed from clones of multiple cell lineages. Conversely, BL6 and 4T1 cells developed spontaneous lung metastases by a small number of clones. Notably, an identical clone of 4T1 cells developed lung metastases in different mice, suggesting the existence of cells with high metastatic potential. Cas9-based transcription recording analysis in a human prostate cancer cell line revealed that specific cells express POU5F1 in response to an anticancer drug and sphere formation. Our findings provide insights into the diversity of cancer cells during tumor progression.
    Keywords:  Cancer stem cell; DNA barcode; Gene expression recording; NANOG; POU5F1; stgRNA
    DOI:  https://doi.org/10.1007/s00018-022-04640-4
  5. Cell Death Dis. 2022 Dec 20. 13(12): 1060
    Blockage of Nrf2 and autophagy by L-selenocystine induces selective death in Nrf2-addicted colorectal cancer cells through p62-Keap-1-Nrf2 axis.
    Wei-Lun Hsu, Chieh-Min Wang, Chao-Ling Yao, Ssu-Ching Chen, Chung-Yi Nien, Yang-Ho Sun, Tsung-Yu Tseng, Yueh-Hsia Luo.
      Persistent Nrf2 activation is typically noted in many cancers, including colorectal cancer (CRC), aiding cancer cells in overcoming growth stress and promoting cancer progression. Sustained Nrf2 activation, which is beneficial for cancer cells, is called "Nrf2 addiction"; it is closely associated with malignancy and poor prognosis in patients with cancer. However, Nrf2 inhibitors may have adverse effects on normal cells. Here, we found that the selenocompound L-selenocystine (SeC) is selectively cytotoxic in the Nrf2-addicted CRC cell line WiDr cells, but not in non-Nrf2-addicted mesenchymal stem cells (MSCs) and normal human colon cells. Another CRC cell line, C2BBe1, which harbored lower levels of Nrf2 and its downstream proteins were less sensitive to SeC, compared with the WiDr cells. We further demonstrated that SeC inhibited Nrf2 and autophagy activation in the CRC cells. Antioxidant GSH pretreatment partially rescued the CRC cells from SeC-induced cytotoxicity and Nrf2 and autophagy pathway inhibition. By contrast, SeC activated Nrf2 and autophagy pathway in non-Nrf2-addicted MSCs. Transfecting WiDr cells with Nrf2-targeting siRNA decreased persistent Nrf2 activation and alleviated SeC cytotoxicity. In KEAP1-knockdown C2BBe1 cells, Nrf2 pathway activation increased SeC sensitivity and cytotoxicity. In conclusion, SeC selectively attacks cancer cells with constitutively activated Nrf2 by reducing Nrf2 and autophagy pathway protein expression through the P62-Nrf2-antioxidant response element axis and eventually trigger cell death.
    DOI:  https://doi.org/10.1038/s41419-022-05512-2
  6. Cancers (Basel). 2022 Dec 15. pii: 6211. [Epub ahead of print]14(24):
    Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma.
    Carmen Salguero-Aranda, Joaquín Olmedo-Pelayo, Enrique de Álava, Ana Teresa Amaral, Juan Díaz-Martín.
      The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm.
    Keywords:  Hippo pathway; TAZ; YAP; gene fusion; sarcoma
    DOI:  https://doi.org/10.3390/cancers14246211
  7. Nat Cancer. 2022 Dec 23.
    YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches.
    Stefano Piccolo, Tito Panciera, Paolo Contessotto, Michelangelo Cordenonsi.
      Our understanding of the function of the transcriptional regulators YAP and TAZ (YAP/TAZ) in cancer is advancing. In this Review, we provide an update on recent progress in YAP/TAZ biology, their regulation by Hippo signaling and mechanotransduction and highlight open questions. YAP/TAZ signaling is an addiction shared by multiple tumor types and their microenvironments, providing many malignant attributes. As such, it represents an important vulnerability that may offer a broad window of therapeutic efficacy, and here we give an overview of the current treatment strategies and pioneering clinical trials.
    DOI:  https://doi.org/10.1038/s43018-022-00473-z
  8. Cancers (Basel). 2022 Dec 13. pii: 6143. [Epub ahead of print]14(24):
    Bio-Mechanical Model of Osteosarcoma Tumor Microenvironment: A Porous Media Approach.
    Yu Hu, Navid Mohammad Mirzaei, Leili Shahriyari.
      Osteosarcoma is the most common malignant bone tumor in children and adolescents with a poor prognosis. To describe the progression of osteosarcoma, we expanded a system of data-driven ODE from a previous study into a system of Reaction-Diffusion-Advection (RDA) equations and coupled it with Biot equations of poroelasticity to form a bio-mechanical model. The RDA system includes the spatio-temporal information of the key components of the tumor microenvironment. The Biot equations are comprised of an equation for the solid phase, which governs the movement of the solid tumor, and an equation for the fluid phase, which relates to the motion of cells. The model predicts the total number of cells and cytokines of the tumor microenvironment and simulates the tumor's size growth. We simulated different scenarios using this model to investigate the impact of several biomedical settings on tumors' growth. The results indicate the importance of macrophages in tumors' growth. Particularly, we have observed a high co-localization of macrophages and cancer cells, and the concentration of tumor cells increases as the number of macrophages increases.
    Keywords:  Biot equations; cancer modeling; osteosarcoma; partial differential equation; poroelasticity; tumor growth; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14246143
  9. Cancers (Basel). 2022 Dec 12. pii: 6120. [Epub ahead of print]14(24):
    A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations.
    Rayhaneh Afjei, Negar Sadeghipour, Sukumar Uday Kumar, Mallesh Pandrala, Vineet Kumar, Sanjay V Malhotra, Tarik F Massoud, Ramasamy Paulmurugan.
      TP53 tumor suppressor gene is a commonly mutated gene in cancer. p53 mediated senescence is critical in preventing oncogenesis in normal cells. Since p53 is a transcription factor, mutations in its DNA binding domain result in the functional loss of p53-mediated cellular pathways. Similarly, nuclear factor erythroid 2-related factor 2 (Nrf2) is another transcription factor that maintains cellular homeostasis by regulating redox and detoxification mechanisms. In glioblastoma (GBM), Nrf2-mediated antioxidant activity is upregulated while p53-mediated senescence is lost, both rendering GBM cells resistant to treatment. To address this, we identified novel Nrf2 inhibitors from bioactive compounds using a molecular imaging biosensor-based screening approach. We further evaluated the identified compounds for their in vitro and in vivo chemotherapy enhancement capabilities in GBM cells carrying different p53 mutations. We thus identified an Nrf2 inhibitor that is effective in GBM cells carrying the p53 (R175H) mutation, a frequent clinically observed hotspot structural mutation responsible for chemotherapeutic resistance in GBM. Combining this drug with low-dose chemotherapies can potentially reduce their toxicity and increase their efficacy by transiently suppressing Nrf2-mediated detoxification function in GBM cells carrying this important p53 missense mutation.
    Keywords:  Nrf2; chemotherapy; glioblastoma; p53; small molecule compounds
    DOI:  https://doi.org/10.3390/cancers14246120
  10. Eur J Cancer. 2022 Nov 26. pii: S0959-8049(22)01770-1. [Epub ahead of print]180 30-51
    Metabolic switch in cancer - Survival of the fittest.
    Hans Raskov, Shruti Gaggar, Asma Tajik, Adile Orhan, Ismail Gögenur.
      Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring of cancer cell metabolism. Driver gene mutations direct malignant cells away from oxidation to maximise energy production and biosynthesis while tumour-secreted factors degrade peripheral tissues to fuel disease progression and initiate metastasis. As it is vital to understand cancer cell metabolism and survival mechanisms, this review discusses the metabolic switch and current drug targets and clinical trials. In the future, metabolic markers may be included when phenotyping individual tumours to improve the therapeutic opportunities for personalised therapy.
    Keywords:  Biosynthesis; Energy production; Hypoxia; Metabolic reprogramming; Nutrient exploitation; Wasting syndrome
    DOI:  https://doi.org/10.1016/j.ejca.2022.11.025
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