bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020–08–16
fiveteen papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance.
  2. FBX8 promotes metastatic dormancy of colorectal cancer in liver.
  3. Epigenetic plasticity in metastatic dormancy: mechanisms and therapeutic implications.
  4. Reversal of pre-existing NGFR-driven tumor and immune therapy resistance.
  5. Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome.
  6. Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis.
  7. ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers.
  8. Studying Lineage Plasticity One Cell at a Time.
  9. Progression and dormancy in metastatic thyroid cancer: concepts and clinical implications.
  10. Microenvironment-Mediated Resistance to Anti-Androgen Therapy.
  11. Linking Matrix Rigidity with EMT and Cancer Invasion.
  12. Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors.
  13. Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network.
  14. NRG1 can promote antiandrogen resistance.
  15. Cytotoxic and antitumor peptides as novel chemotherapeutics.
  1. Nat Commun. 2020 Aug 13. 11(1): 4053
    PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance.
    Elodie Montaudon, Joanna Nikitorowicz-Buniak, Laura Sourd, Ludivine Morisset, Rania El Botty, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Fariba Nemati, Sophie Vacher, Walid Chemlali, Julien Masliah-Planchon, Sophie Château-Joubert, Camilla Rega, Mariana Ferreira Leal, Nikiana Simigdala, Sunil Pancholi, Ricardo Ribas, André Nicolas, Didier Meseure, Anne Vincent-Salomon, Cécile Reyes, Audrey Rapinat, David Gentien, Thibaut Larcher, Mylène Bohec, Sylvain Baulande, Virginie Bernard, Didier Decaudin, Florence Coussy, Muriel Le Romancer, Guillaume Dutertre, Zakia Tariq, Paul Cottu, Keltouma Driouch, Ivan Bièche, Lesley-Ann Martin, Elisabetta Marangoni.
      A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment.
    DOI:  https://doi.org/10.1038/s41467-020-17697-1
  2. Cell Death Dis. 2020 Aug 14. 11(8): 622
    FBX8 promotes metastatic dormancy of colorectal cancer in liver.
    Xiaohui Zhu, Feifei Wang, Xuehui Wu, Zhou Li, Zhizhi Wang, Xiaoli Ren, Yangshu Zhou, Fuyao Song, Yunshi Liang, Zhicheng Zeng, Wangjun Liao, Yanqing Ding, Wenting Liao, Li Liang.
      Patients with colorectal cancer (CRC) often develop malignant regrowth of metastatic dormant tumor cells in liver years after primary treatment. FBX8 is involved in suppressing tumor metastasis. Short-term chemotherapy experiments and liver metastasis mice model of orthotopic injection into the cecum were performed to construct the dormant models. GST-pull-down assay, Co-IP and immunofluorescence were used to confirm the bindings among FBX8 and its substrates. FBX8 upregulated the expression of epithelial and stemness markers, while downregulated the expression of mesenchymal and proliferative markers associated with tumor cell dormancy. FBX8 promoted the maintenance of metastatic dormancy of CRC cells. Mechanistically, FBX8 directly bound to HIF-1α, CDK4 and C-myc through its Sec7 domain and led to the ubiquitin degradation of these proteins, thereby inhibiting cell cycle progression, proliferation, angiogenesis, and metastasis. Clinically, FBX8 expression was negatively correlated with the HIF-1α, CDK4, and c-Myc in CRC tissues. Our study reveals a novel mechanism of FBX8 in regulating tumor metastatic dormancy in liver and provides new strategies for the treatment of CRC metastasis.
    DOI:  https://doi.org/10.1038/s41419-020-02870-7
  3. Ann Transl Med. 2020 Jul;8(14): 903
    Epigenetic plasticity in metastatic dormancy: mechanisms and therapeutic implications.
    Nathaniel J Robinson, Kimberly A Parker, William P Schiemann.
      The overwhelming majority of cancer-associated morbidity and mortality can be ascribed to metastasis. Metastatic disease frequently presents in a delayed fashion following initial diagnosis and treatment, requiring that disseminated cancer cells (DCCs) spread early in tumor progression and persist in a dormant state at metastatic sites. To accomplish this feat, DCCs exhibit substantial phenotypic plasticity that is mediated by the epigenetic regulation of dormancy programs in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) cues. The epigenome is a dynamic landscape that encompasses transcriptional regulation via alteration of chromatin architecture, posttranscriptional RNA processing, and the diverse functions carried out by noncoding RNAs. Signals converging on DCCs are transduced through epigenetic effectors. Conversely, epigenetic regulation of gene expression controls the crosstalk between DCCs and cells of the metastatic niche, a phenomenon that is essential for the institution of dormant phenotypes. Importantly, epigenetic effectors can be targeted therapeutically, and the development of novel epigenetic therapies may provide new inroads to combating recurrent metastatic disease. Here we provide an overview of the dynamics of metastatic dormancy and summarize our current understanding of the intersections between dormancy and the epigenome, both mechanistically and therapeutically.
    Keywords:  Dormancy; epigenetics; long non-coding RNAs (lncRNAs); metastasis; targeted therapy
    DOI:  https://doi.org/10.21037/atm.2020.02.177
  4. Nat Commun. 2020 Aug 07. 11(1): 3946
    Reversal of pre-existing NGFR-driven tumor and immune therapy resistance.
    Julia Boshuizen, David W Vredevoogd, Oscar Krijgsman, Maarten A Ligtenberg, Stephanie Blankenstein, Beaunelle de Bruijn, Dennie T Frederick, Juliana C N Kenski, Mara Parren, Marieke Brüggemann, Max F Madu, Elisa A Rozeman, Ji-Ying Song, Hugo M Horlings, Christian U Blank, Alexander C J van Akkooi, Keith T Flaherty, Genevieve M Boland, Daniel S Peeper.
      Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-020-17739-8
  5. Nat Commun. 2020 Aug 07. 11(1): 3945
    Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome.
    Valeria Capaci, Lorenzo Bascetta, Marco Fantuz, Galina V Beznoussenko, Roberta Sommaggio, Valeria Cancila, Andrea Bisso, Elena Campaner, Alexander A Mironov, Jacek R Wiśniewski, Luisa Ulloa Severino, Denis Scaini, Fleur Bossi, Jodi Lees, Noa Alon, Ledia Brunga, David Malkin, Silvano Piazza, Licio Collavin, Antonio Rosato, Silvio Bicciato, Claudio Tripodo, Fiamma Mantovani, Giannino Del Sal.
      TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.
    DOI:  https://doi.org/10.1038/s41467-020-17596-5
  6. Nat Commun. 2020 Aug 13. 11(1): 4055
    Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis.
    Matthew E Bechard, Rana Smalling, Akimasa Hayashi, Yi Zhong, Anna E Word, Sydney L Campbell, Amanda V Tran, Vivian L Weiss, Christine Iacobuzio-Donahue, Kathryn E Wellen, Oliver G McDonald.
      Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.
    DOI:  https://doi.org/10.1038/s41467-020-17839-5
  7. Nat Commun. 2020 Aug 07. 11(1): 3965
    ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation to enhance drug resistance in breast cancers.
    Wei Wang, Mingqi Li, Suriyan Ponnusamy, Yayun Chi, Jingyan Xue, Beshoy Fahmy, Meiyun Fan, Gustavo A Miranda-Carboni, Ramesh Narayanan, Jiong Wu, Zhao-Hui Wu.
      Dysregulated Wnt/β-catenin activation plays a critical role in cancer progression, metastasis, and drug resistance. Genotoxic agents such as radiation and chemotherapeutics have been shown to activate the Wnt/β-catenin signaling although the underlying mechanism remains incompletely understood. Here, we show that genotoxic agent-activated Wnt/β-catenin signaling is independent of the FZD/LRP heterodimeric receptors and Wnt ligands. OTULIN, a linear linkage-specific deubiquitinase, is essential for the DNA damage-induced β-catenin activation. OTULIN inhibits linear ubiquitination of β-catenin, which attenuates its Lys48-linked ubiquitination and proteasomal degradation upon DNA damage. The association with β-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl. Inhibiting OTULIN or Wnt/β-catenin sensitizes triple-negative breast cancer xenograft tumors to chemotherapeutics and reduces metastasis. Increased OTULIN levels are associated with aggressive molecular subtypes and poor survival in breast cancer patients. Thus, OTULIN-mediated Wnt/β-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers.
    DOI:  https://doi.org/10.1038/s41467-020-17770-9
  8. Cancer Cell. 2020 Aug 10. pii: S1535-6108(20)30362-7. [Epub ahead of print]38(2): 150-152
    Studying Lineage Plasticity One Cell at a Time.
    Benjamin J Drapkin, John D Minna.
      The development and consequences of lineage plasticity during tumorigenesis have remained mysterious due to the limits of single-cell analysis. In this issue of Cancer Cell, LaFave et al. and Marjanovic et al. identify highly plastic subpopulations within lung adenocarcinoma that may underlie intratumoral lineage heterogeneity, metastasis, and acquired resistance to chemotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2020.07.001
  9. Endocrine. 2020 Aug 11.
    Progression and dormancy in metastatic thyroid cancer: concepts and clinical implications.
    Neel Rajan, Tilak Khanal, Matthew D Ringel.
      Distant metastasis classically has been defined as a late-stage event in cancer progression. However, it has become clear that metastases also may occur early in the "lifetime" of a cancer and that they may remain stable at distant sites. This stability of metastatic cancer deposits has been termed "metastatic dormancy" or, as we term it, "metastatic progression dormancy" as the progression either may reflect growth of already existing metastases or new cancer spread. Biologically, dormancy is the presence of nongrowing, static metastatic cells that survive over time. Clinically, dormancy is defined by stability in tumor markers, imaging, and clinical course. Metastatic well-differentiated thyroid cancer offers an excellent tumor type to understand these processes for several reasons: (1) primary therapy often includes removal of the entire gland with ablation of residual normal tissue thereby removing one source for new metastases; (2) the presence of a sensitive biochemical and radiographic monitoring tests enabling monitoring of metastasis throughout the progression process; and (3) its tendency toward prolonged clinical dormancy that can last for years or decades be followed by progression. This latter factor provides opportunities to define therapeutic targets and/or markers of progression. In this review, we will discuss concepts of metastatic progression dormancy and the factors that drive both long-term stability and loss of dormancy with a focus on thyroid cancer.
    Keywords:  Dormancy; Metastasis; Progression; Thyroid cancer
    DOI:  https://doi.org/10.1007/s12020-020-02453-8
  10. Cancer Cell. 2020 Aug 10. pii: S1535-6108(20)30368-8. [Epub ahead of print]38(2): 155-157
    Microenvironment-Mediated Resistance to Anti-Androgen Therapy.
    Jacob J Orme, Haojie Huang.
      In this issue of Cancer Cell, Zhang et al. expose new possibilities for targeting castration-resistant prostate cancer (CRPC). Activation of the HER2/HER3 axis by cancer-associated fibroblast-secreted NRG1 mediates castration resistance, recommending novel applications of clinical anti-NRG1/HER3 therapeutics in treating CRPC.
    DOI:  https://doi.org/10.1016/j.ccell.2020.07.007
  11. Dev Cell. 2020 Aug 10. pii: S1534-5807(20)30540-2. [Epub ahead of print]54(3): 293-295
    Linking Matrix Rigidity with EMT and Cancer Invasion.
    Manon Ros, Margaux Sala, Frédéric Saltel.
      The extracellular matrix (ECM) plays a major role in cancer progression through its increased deposition and alignment. In this issue of Developmental Cell, Fattet et al. reveal a pathway in which ECM stiffness promotes EPHA2/LYN complex activation, leading to TWIST1 nuclear localization and triggering EMT in breast cancer.
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.032
  12. Cancers (Basel). 2020 Aug 07. pii: E2210. [Epub ahead of print]12(8):
    Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors.
    Shu-Chun Chang, Wayne Hsu, Emily Chia-Yu Su, Chin-Sheng Hung, Jeak Ling Ding.
      The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.
    Keywords:  CCND2; FBXL8 SCF E3 ubiquitin ligase; IRF5; breast cancer (BRCA) and metastasis; pro-tumorigenic microenvironment
    DOI:  https://doi.org/10.3390/cancers12082210
  13. Leukemia. 2020 Aug 07.
    Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network.
    Xiaorong Gu, Rita Tohme, Benjamin Tomlinson, Nneha Sakre, Metis Hasipek, Lisa Durkin, Caroline Schuerger, Dale Grabowski, Asmaa M Zidan, Tomas Radivoyevitch, Changjin Hong, Hetty Carraway, Betty Hamilton, Ronald Sobecks, Bhumika Patel, Babal K Jha, Eric D Hsi, Jaroslaw Maciejewski, Yogen Saunthararajah.
      Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a deoxynucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). Here, upon serial analyses of DNMT1 levels in patients' bone marrows on-therapy, we found DNMT1 was not depleted at relapse. Showing why, bone marrows at relapse exhibited shifts in expression of key pyrimidine metabolism enzymes in directions adverse to pro-drug activation. Further investigation revealed the origin of these shifts. Pyrimidine metabolism is a network that senses and regulates deoxynucleotide amounts. Deoxynucleotide amounts were disturbed by single exposures to decitabine or 5-azacytidine, via off-target depletion of thymidylate synthase and ribonucleotide reductase respectively. Compensating pyrimidine metabolism shifts peaked 72-96 h later. Continuous pro-drug exposures stabilized these adaptive metabolic responses to thereby prevent DNMT1-depletion and permit exponential leukemia out-growth as soon as day 40. The consistency of the acute metabolic responses enabled exploitation: simple treatment modifications in xenotransplant models of chemorefractory leukemia extended noncytotoxic DNMT1-depletion and leukemia control by several months. In sum, resistance to decitabine and 5-azacytidine originates from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited.
    DOI:  https://doi.org/10.1038/s41375-020-1003-x
  14. Nat Rev Urol. 2020 Aug 11.
    NRG1 can promote antiandrogen resistance.
    Rebecca Kelsey.
      
    DOI:  https://doi.org/10.1038/s41585-020-0370-4
  15. Nat Prod Rep. 2020 Aug 10.
    Cytotoxic and antitumor peptides as novel chemotherapeutics.
    Xin Luan, Ye Wu, Yi-Wen Shen, Hong Zhang, Yu-Dong Zhou, Hong-Zhuan Chen, Dale G Nagle, Wei-Dong Zhang.
      Covering: up to 2020Treatment resistance and drug-induced refractory malignancies pose significant challenges for current chemotherapy drugs. There have been increasing research efforts aimed at developing novel chemotherapeutics, especially from natural products and related derivatives. Natural cytotoxic peptides, an emerging source of chemotherapeutics, have exhibited the advantage of overcoming drug resistance and displayed broad-spectrum antitumor activities in the clinic. This highlight examines the increasingly popular cytotoxic peptides from isolated natural products. In-depth review of several peptides provides examples for how this novel strategy can lead to the improved anti-tumor effects. The mechanisms and current application of representative natural cytotoxic peptides (NCPs) have also been discussed, with a particular focus on future directions for interdisciplinary research.
    DOI:  https://doi.org/10.1039/d0np00019a
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