bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022‒10‒02
eleven papers selected by
Rana Gbyli
Yale University
  1. ecDNA Inheritance Supports Tumor Heterogeneity and Evolution.
  2. Loss of SNAI1 induces cellular plasticity in invasive triple-negative breast cancer cells.
  3. Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.
  4. A Limited Cell Population Supports Melanoma Tumor Growth.
  5. Progression of Glioblastoma Is Impaired by VEGF Inhibition and Imipramine.
  6. BCSCdb: a database of biomarkers of cancer stem cells.
  7. Somatic mosaicism rewires transcriptional and epigenetic states in clonal hematopoiesis.
  8. Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.
  9. Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability.
  10. A mechanism for oxidative damage repair at gene regulatory elements.
  11. [Dormancy: There and Back Again].
  1. Cancer Discov. 2022 Sep 30. OF1
    ecDNA Inheritance Supports Tumor Heterogeneity and Evolution.
      Segregation of extrachromosomal DNA (ecDNA) is random and leads to extensive copy-number heterogeneity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-176
  2. Cell Death Dis. 2022 Sep 28. 13(9): 832
    Loss of SNAI1 induces cellular plasticity in invasive triple-negative breast cancer cells.
    Chrysoula Tsirigoti, Mohamad Moustafa Ali, Varun Maturi, Carl-Henrik Heldin, Aristidis Moustakas.
      The transcription factor SNAI1 mediates epithelial-mesenchymal transition, fibroblast activation and controls inter-tissue migration. High SNAI1 expression characterizes metastatic triple-negative breast carcinomas, and its knockout by CRISPR/Cas9 uncovered an epithelio-mesenchymal phenotype accompanied by reduced signaling by the cytokine TGFβ. The SNAI1 knockout cells exhibited plasticity in differentiation, drifting towards the luminal phenotype, gained stemness potential and could differentiate into acinar mammospheres in 3D culture. Loss of SNAI1 de-repressed the transcription factor FOXA1, a pioneering factor of mammary luminal progenitors. FOXA1 induced a specific gene program, including the androgen receptor (AR). Inhibiting AR via a specific antagonist regenerated the basal phenotype and blocked acinar differentiation. Thus, loss of SNAI1 in the context of triple-negative breast carcinoma cells promotes an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the dual transcriptional action of FOXA1 and AR. This function of SNAI1 provides means to separate cell invasiveness from progenitor cell de-differentiation as independent cellular programs.
    DOI:  https://doi.org/10.1038/s41419-022-05280-z
  3. Nat Commun. 2022 Sep 24. 13(1): 5614
    Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.
    Yoshihisa Kobayashi, Geoffrey R Oxnard, Elizabeth F Cohen, Navin R Mahadevan, Joao V Alessi, Yin P Hung, Arrien A Bertram, David E Heppner, Mauricio F Ribeiro, Karina P Sacardo, Rodrigo Saddi, Mariana P Macedo, Rafael B Blasco, Jiaqi Li, Kari J Kurppa, Tom Nguyen, Emma Voligny, Guruprasad Ananda, Roberto Chiarle, Artur Katz, Michael Y Tolstorukov, Lynette M Sholl, Pasi A Jänne.
      The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.
    DOI:  https://doi.org/10.1038/s41467-022-33210-2
  4. Cancer Discov. 2022 Sep 30. OF1
    A Limited Cell Population Supports Melanoma Tumor Growth.
      Melanoma growth is supported by a narrow cell population that exhibits an embryonic transcriptional program.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-174
  5. Cancer Discov. 2022 Sep 30. OF1
    Progression of Glioblastoma Is Impaired by VEGF Inhibition and Imipramine.
      Dual VEGF inhibitor and tricyclic antidepressant treatment reduces GBM tumor growth and promotes immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-173
  6. Database (Oxford). 2022 Sep 28. pii: baac082. [Epub ahead of print]2022
    BCSCdb: a database of biomarkers of cancer stem cells.
    Shazia Firdous, Abhirupa Ghosh, Sudipto Saha.
      Cancer stem cells (CSCs) are a small heterogeneous population present within the tumor cells exhibiting self-renewal properties. CSCs have been demonstrated to elicit an important role in cancer recurrence, metastasis and drug resistance. CSCs are distinguished from cancer cell populations based on their molecular profiling or expression of distinct CSC biomarker(s). Recently, a huge amount of omics data have been generated for the characterization of CSCs, which enables distinguishing CSCs in different cancers. Here, we report biomarkers of the Cancer Stem Cells database (BCSCdb), a repository of information about CSC biomarkers. BCSCdb comprises CSC biomarkers collected from PubMed literature where these are identified using high-throughput and low-throughput methods. Each biomarker is provided with two different scores: the first is a confidence score to give confidence to reported CSC biomarkers based on the experimental method of detection in CSCs. The second is the global score to identify the global CSC biomarkers across 10 different types of cancer. This database contains three tables containing information about experimentally validated CSC biomarkers or genes, therapeutic target genes of CSCs and CSC biomarkers interactions. It contains information on three types of markers: high-throughput marker (HTM-8307), high-throughput marker validated by the low-throughput method (283) and low-throughput marker (LTM-525). A total of 171 low-throughput biomarkers were identified in primary tissue referred to as clinical biomarkers. Moreover, it contains 445 target genes for CSC therapeutics, 10 biomarkers targeted by clinical trial drugs in CSCs and 5 different types of interaction data for CSC biomarkers. BCSCdb is an online resource for CSC biomarkers, which will be immensely helpful in the cancer research community and is freely available. Database URL: http://dibresources.jcbose.ac.in/ssaha4/bcscdb.
    DOI:  https://doi.org/10.1093/database/baac082
  7. Nat Genet. 2022 Sep 26.
    Somatic mosaicism rewires transcriptional and epigenetic states in clonal hematopoiesis.
      
    DOI:  https://doi.org/10.1038/s41588-022-01181-1
  8. Methods Mol Biol. 2023 ;2572 117-127
    Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.
    Henry Ruiz-Garcia, Natanael Zarco, Fumihiro Watanabe, Virginea De Araujo Farias, Paola Suarez-Meade, Hugo Guerrero-Cazares, Jaime Imitola, Alfredo Quinones-Hinojosa, Daniel Trifiletti.
      Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics.
    Keywords:  Glioblastoma; Neurosphere; Organoids; Organotypics; Stem cell
    DOI:  https://doi.org/10.1007/978-1-0716-2703-7_9
  9. Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01234-7. [Epub ahead of print]40(13): 111397
    Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability.
    Dan Sarni, Sonia Barroso, Alon Shtrikman, Michal Irony-Tur Sinai, Yifat S Oren, Andrés Aguilera, Batsheva Kerem.
      DNA replication is a complex process tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Replication stress is commonly associated with slow and stalled replication forks. Recently, accelerated replication has emerged as a non-canonical form of replication stress. However, the molecular basis underlying fork acceleration is largely unknown. Here, we show that mutated HRAS activation leads to increased topoisomerase 1 (TOP1) expression, causing aberrant replication fork acceleration and DNA damage by decreasing RNA-DNA hybrids or R-loops. In these cells, restoration of TOP1 expression or mild replication inhibition rescues the perturbed replication and reduces DNA damage. Furthermore, TOP1 or RNaseH1 overexpression induces accelerated replication and DNA damage, highlighting the importance of TOP1 equilibrium in regulating R-loop homeostasis to ensure faithful DNA replication and genome integrity. Altogether, our results dissect a mechanism of oncogene-induced DNA damage by aberrant replication fork acceleration.
    Keywords:  CP: Molecular biology; DNA replication; R loops; genomic instability; oncogenes; replication stress; topoisomerase 1
    DOI:  https://doi.org/10.1016/j.celrep.2022.111397
  10. Nature. 2022 Sep;609(7929): 1038-1047
    A mechanism for oxidative damage repair at gene regulatory elements.
    Swagat Ray, Arwa A Abugable, Jacob Parker, Kirsty Liversidge, Nelma M Palminha, Chunyan Liao, Adelina E Acosta-Martin, Cleide D S Souza, Mateusz Jurga, Ian Sudbery, Sherif F El-Khamisy.
      Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation1,2. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100 bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate-early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.
    DOI:  https://doi.org/10.1038/s41586-022-05217-8
  11. Mol Biol (Mosk). 2022 Sep-Oct;56(5):56(5): 808-831
    [Dormancy: There and Back Again].
    E S Pshennikova, A S Voronina.
      Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body. These cells are resistant to therapy that can destroy intensely dividing cells and to the host immune system. A cascade of reactions that allows cells to ener and exit dormancy is triggered by regulatory factors from the microenvironment in niches that harbor the cells. A ratio of forbidding and permitting signals dictates whether the cells become dormant or start proliferation. The only difference between the cell dormancy regulation in normal and pathological conditions is that pathogens, mycobacteria, and cancer cells can influence their own fate by changing their microenvironment. Certain mechanisms of these processes are considered in the review.
    Keywords:  Mycobacterium tuberculosis; dormancy; mesenchymal stem cells; metastasis; metastatic niches; tumor cells
    DOI:  https://doi.org/10.31857/S0026898422050111
This page is being maintained by Thomas Krichel. It was last updated on 2022‒10‒02 at 19:27:44.