bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2021–06–27
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis.
  2. Molecular determinants of response to PD-L1 blockade across tumor types.
  3. Modeling colorectal cancers using multidimensional organoids.
  4. A community challenge to evaluate RNA-seq, fusion detection, and isoform quantification methods for cancer discovery.
  5. Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.
  6. Temporal coding of ERK signalling in β-cells.
  7. A bird's eye view of fibroblast heterogeneity: A pan-disease, pan-cancer perspective.
  1. Sci Signal. 2021 Jun 22. pii: eabe6156. [Epub ahead of print]14(688):
    TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis.
    Mary L Uribe, Maik Dahlhoff, Rajbir N Batra, Nishanth B Nataraj, Yuya Haga, Diana Drago-Garcia, Ilaria Marrocco, Arunachalam Sekar, Soma Ghosh, Itay Vaknin, Sacha Lebon, Lior Kramarski, Yasuo Tsutsumi, Inpyo Choi, Oscar M Rueda, Carlos Caldas, Yosef Yarden.
      Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mammary gland development in mice. Although the gene TSHZ2 localizes to a locus (20q13.2) that is frequently amplified in breast cancer, we found that hypermethylation of its promoter correlated with down-regulation of TSHZ2 expression in patients. Yeast two-hybrid screens and protein-fragment complementation assays in mammalian cells indicated that TSHZ2 nucleated a multiprotein complex containing PRC1/Ase1, cyclin B1, and additional proteins that regulate cytokinesis. TSHZ2 increased the inhibitory phosphorylation of PRC1, a key driver of mitosis, mediated by cyclin-dependent kinases. Furthermore, similar to the tumor suppressive transcription factor p53, TSHZ2 inhibited transcription from the PRC1 promoter. By recognizing DDGs as a distinct group in the transcriptional response to EGF, our findings uncover a group of tumor suppressors and reveal a role for TSHZ2 in cell cycle regulation.
    DOI:  https://doi.org/10.1126/scisignal.abe6156
  2. Nat Commun. 2021 Jun 25. 12(1): 3969
    Molecular determinants of response to PD-L1 blockade across tumor types.
    Romain Banchereau, Ning Leng, Oliver Zill, Ethan Sokol, Gengbo Liu, Dean Pavlick, Sophia Maund, Li-Fen Liu, Edward Kadel, Nicole Baldwin, Suchit Jhunjhunwala, Dorothee Nickles, Zoe June Assaf, Daniel Bower, Namrata Patil, Mark McCleland, David Shames, Luciana Molinero, Mahrukh Huseni, Shomyseh Sanjabi, Craig Cummings, Ira Mellman, Sanjeev Mariathasan, Priti Hegde, Thomas Powles.
      Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1+ tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.
    DOI:  https://doi.org/10.1038/s41467-021-24112-w
  3. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00021-X. [Epub ahead of print]151 345-383
    Modeling colorectal cancers using multidimensional organoids.
    Ibrahim M Sayed, Amer Ali Abd El-Hafeez, Priti P Maity, Soumita Das, Pradipta Ghosh.
      Organoids have revolutionized cancer research as highly adaptable models that enable an array of experimental techniques to interrogate tissue morphology and function. Because they preserve the genetic, phenotypic, and behavioral traits of their source tissue, organoids have gained traction as the most relevant models for drug discovery, tracking therapeutic response and for personalized medicine. As organoids are indisputably becoming a mainstay of cancer research, this review specifically addresses how colon-derived organoids can be perfected as multidimensional, scalable, reproducible models of healthy, pre-neoplastic and neoplastic conditions of the colon and for use in high-throughput "Phase-0" human clinical trials-in-a-dish.
    Keywords:  CRC; Clinical trials; Coculture; Colon organoid; Drug screening; Multidimensional
    DOI:  https://doi.org/10.1016/bs.acr.2021.02.005
  4. Cell Syst. 2021 Jun 16. pii: S2405-4712(21)00207-6. [Epub ahead of print]
    A community challenge to evaluate RNA-seq, fusion detection, and isoform quantification methods for cancer discovery.
    SMC-RNA Challenge Participants
      The accurate identification and quantitation of RNA isoforms present in the cancer transcriptome is key for analyses ranging from the inference of the impacts of somatic variants to pathway analysis to biomarker development and subtype discovery. The ICGC-TCGA DREAM Somatic Mutation Calling in RNA (SMC-RNA) challenge was a crowd-sourced effort to benchmark methods for RNA isoform quantification and fusion detection from bulk cancer RNA sequencing (RNA-seq) data. It concluded in 2018 with a comparison of 77 fusion detection entries and 65 isoform quantification entries on 51 synthetic tumors and 32 cell lines with spiked-in fusion constructs. We report the entries used to build this benchmark, the leaderboard results, and the experimental features associated with the accurate prediction of RNA species. This challenge required submissions to be in the form of containerized workflows, meaning each of the entries described is easily reusable through CWL and Docker containers at https://github.com/SMC-RNA-challenge. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  Cancer; Cloud compute; DREAM Challenge; RNA fusion; RNA-seq; benchmark; crowd-sourced; evaluation; isoform quantification
    DOI:  https://doi.org/10.1016/j.cels.2021.05.021
  5. Commun Biol. 2021 Jun 24. 4(1): 783
    Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.
    Sammy Alhassen, Siwei Chen, Lamees Alhassen, Alvin Phan, Mohammad Khoudari, Angele De Silva, Huda Barhoosh, Zitong Wang, Chelsea Parrocha, Emily Shapiro, Charity Henrich, Zicheng Wang, Leon Mutesa, Pierre Baldi, Geoffrey W Abbott, Amal Alachkar.
      Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.
    DOI:  https://doi.org/10.1038/s42003-021-02255-2
  6. Nat Rev Endocrinol. 2021 Jun 24.
    Temporal coding of ERK signalling in β-cells.
    Mark O Huising, John G Albeck.
      
    DOI:  https://doi.org/10.1038/s41574-021-00527-9
  7. Immunol Rev. 2021 Jun 23.
    A bird's eye view of fibroblast heterogeneity: A pan-disease, pan-cancer perspective.
    Rachana N Pradhan, Akshay T Krishnamurty, Anne L Fletcher, Shannon J Turley, Sören Müller.
      Fibroblasts, custodians of tissue architecture and function, are no longer considered a monolithic entity across tissues and disease indications. Recent advances in single-cell technologies provide an unrestricted, high-resolution view of fibroblast heterogeneity that exists within and across tissues. In this review, we summarize a compendium of single-cell transcriptomic studies and provide a comprehensive accounting of fibroblast subsets, many of which have been described to occupy specific niches in tissues at homeostatic and pathologic states. Understanding this heterogeneity is particularly important in the context of cancer, as the diverse cancer-associated fibroblast (CAF) phenotypes in the tumor microenvironment (TME) are directly impacted by the expression phenotypes of their predecessors. Relationships between these heterogeneous populations often accompany and influence response to therapy in cancer and fibrosis. We further highlight the importance of integrating single-cell studies to deduce common fibroblast phenotypes across disease states, which will facilitate the identification of common signaling pathways, gene regulatory programs, and cell surface markers that are going to advance drug discovery and targeting.
    Keywords:  cancer; fibroblast heterogeneity; fibrosis; modulation of cancer-associated fibroblasts; single-cell transcriptomics
    DOI:  https://doi.org/10.1111/imr.12990
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