bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020–03–15
24 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Autophagy Suppresses Breast Cancer Metastasis.
  2. Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer.
  3. Nanosponges of circulating tumor-derived exosomes for breast cancer metastasis inhibition.
  4. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy.
  5. The non-receptor tyrosine phosphatase type 14 blocks caveolin-1-enhanced cancer cell metastasis.
  6. KISS1 in metastatic cancer research and treatment: potential and paradoxes.
  7. Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
  8. Glutaminase-1 (GLS1) inhibition limits metastatic progression in osteosarcoma.
  9. Feedback analysis identifies a combination target for overcoming adaptive resistance to targeted cancer therapy.
  10. Minimal barriers to invasion during human colorectal tumor growth.
  11. IL33 is a key driver of treatment resistance of cancer.
  12. Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer.
  13. Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2α drives metastasis of hepatocellular carcinoma.
  14. Gastrin Blocks Symmetric Stem-Cell Division and Gastric Tumorigenesis.
  15. Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours.
  16. PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells.
  17. Lineage plasticity in cancer: a shared pathway of therapeutic resistance.
  18. Tweaking the DNA of myeloid cells curbs cancer spread.
  19. Ru@CeO2 yolk shell nanozymes: Oxygen supply in situ enhanced dual chemotherapy combined with photothermal therapy for orthotopic/subcutaneous colorectal cancer.
  20. Inappropriate use of progression-free survival in cancer drug approvals.
  21. Inflammatory microenvironment remodelling by tumour cells after radiotherapy.
  22. Time-lapse single-cell transcriptomics reveals modulation of histone H3 for dormancy breaking in fission yeast.
  23. Long non-coding RNAs regulate drug resistance in cancer.
  24. Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs.
  1. Dev Cell. 2020 Mar 09. pii: S1534-5807(20)30101-5. [Epub ahead of print]52(5): 542-544
    Autophagy Suppresses Breast Cancer Metastasis.
    Benjamin N Ostendorf, Sohail F Tavazoie.
      Cancer cells need to acquire specific molecular traits in order to spread to distant organs. In this issue of Developmental Cell, Marsh et al. show that autophagy restricts the outgrowth of breast cancer metastases in contrast to its impact on primary tumor progression.
    DOI:  https://doi.org/10.1016/j.devcel.2020.02.005
  2. Cell Stem Cell. 2020 Mar 06. pii: S1934-5909(20)30061-8. [Epub ahead of print]
    Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer.
    Arianna Fumagalli, Koen C Oost, Lennart Kester, Jessica Morgner, Laura Bornes, Lotte Bruens, Lisa Spaargaren, Maria Azkanaz, Tim Schelfhorst, Evelyne Beerling, Maria C Heinz, Daniel Postrach, Danielle Seinstra, Anieta M Sieuwerts, John W M Martens, Stefan van der Elst, Martijn van Baalen, Debajit Bhowmick, Nienke Vrisekoop, Saskia I J Ellenbroek, Saskia J E Suijkerbuijk, Hugo J Snippert, Jacco van Rheenen.
      Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5- and formed distant metastases in which Lgr5+ CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5- cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors.
    Keywords:  Lgr5; cancer stem cells; circulating tumor cells; colorectal cancer; intravital microscopy; metastasis; microenvironment; plasticity
    DOI:  https://doi.org/10.1016/j.stem.2020.02.008
  3. Biomaterials. 2020 Mar 04. pii: S0142-9612(20)30178-2. [Epub ahead of print]242 119932
    Nanosponges of circulating tumor-derived exosomes for breast cancer metastasis inhibition.
    Hao Ye, Kaiyuan Wang, Qi Lu, Jian Zhao, Menglin Wang, Qiming Kan, Haotian Zhang, Yongjun Wang, Zhonggui He, Jin Sun.
      Breast cancer contributes to high mortality rates as a result of metastasis. Tumor-derived exosomes facilitate the development of the premetastatic environment, interacting and inhibiting the normal function of immune cells, thereby forming an immunosuppressive microenvironment for tumor metastasis. Herein, the platelet and neutrophil hybrid cell membrane (PNM) was embellished on a gold nanocage (AuNC) surface called nanosponges and nanokillers (NSKs). NSKs can simultaneously capture and clear the circulating tumor cells (CTCs) and tumor-derived exosomes via high-affinity membrane adhesion receptors, effectively cutting off the connection between exosomes and immune cells. Bionic NSK is loaded with doxorubicin (DOX) and indocyanine green (ICG) for synergic chemo-photothermal therapy. NSKs show greater cellular uptake, deeper tumor penetration, and higher cytotoxicity to tumor cells in comparison to non-coated AuNCs or single-coated AuNCs in vitro. In vivo, the multipurpose NSKs could not only completely ablate the primary tumor but also inhibit breast cancer metastasis with high efficiency in xenograft and orthotopic breast tumor-bearing models. Thus, NSKs could be a promising nanomedicine for the future clinical intervention of breast cancer metastasis.
    Keywords:  Biomimetic; Breast cancer metastasis; Circulating tumor cells; Exosomes; Platelet-neutrophil hybrid membrane
    DOI:  https://doi.org/10.1016/j.biomaterials.2020.119932
  4. Proc Natl Acad Sci U S A. 2020 Mar 11. pii: 201921445. [Epub ahead of print]
    Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy.
    Xiaodong Wang, Xiaohui Yang, Chang Zhang, Yang Wang, Tianyou Cheng, Liqiang Duan, Zhou Tong, Shuguang Tan, Hangjie Zhang, Phei Er Saw, Yinmin Gu, Jinhua Wang, Yibi Zhang, Lina Shang, Yajuan Liu, Siyuan Jiang, Bingxue Yan, Rong Li, Yue Yang, Jie Yu, Yunzhao Chen, George Fu Gao, Qinong Ye, Shan Gao.
      The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.
    Keywords:  biomarker; drug resistance; tumor cell-intrinsic PD-1; tumor cell-intrinsic PD-L1; tumor suppressor
    DOI:  https://doi.org/10.1073/pnas.1921445117
  5. Oncogene. 2020 Mar 09.
    The non-receptor tyrosine phosphatase type 14 blocks caveolin-1-enhanced cancer cell metastasis.
    Natalia I Díaz-Valdivia, Jorge Díaz, Pamela Contreras, América Campos, Victoria Rojas-Celis, Renato A Burgos-Ravanal, Lorena Lobos-González, Vicente A Torres, Viviana I Perez, Balz Frei, Lisette Leyton, Andrew F G Quest.
      Caveolin-1 (CAV1) enhanced migration, invasion, and metastasis of cancer cells is inhibited by co-expression of the glycoprotein E-cadherin. Although the two proteins form a multiprotein complex that includes β-catenin, it remained unclear how this would contribute to blocking the metastasis promoting function of CAV1. Here, we characterized by mass spectrometry the protein composition of CAV1 immunoprecipitates from B16F10 murine melanoma cells expressing or not E-cadherin. The novel protein tyrosine phosphatase PTPN14 was identified by mass spectrometry analysis exclusively in co-immunoprecipitates of CAV1 with E-cadherin. Interestingly, PTPN14 is implicated in controlling metastasis, but only few known PTPN14 substrates exist. We corroborated by western blotting experiments that PTPN14 and CAV1 co-inmunoprecipitated in the presence of E-cadherin in B16F10 melanoma and other cancer cells. Moreover, the CAV1(Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine-14, as well as suppressed CAV1-enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29(US)] and breast cancer (MDA-MB-231) cell lines. Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo. In summary, we identify here CAV1 as a novel substrate for PTPN14 and show that overexpression of this phosphatase suffices to reduce CAV1-induced metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-1242-3
  6. Cancer Metastasis Rev. 2020 Mar 09.
    KISS1 in metastatic cancer research and treatment: potential and paradoxes.
    Thuc Ly, Sitaram Harihar, Danny R Welch.
      The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinical development in the cancer therapeutic and biomarker space. Research has focused on amino acid residues 68-121 (kisspeptin 54), binding to the KISS1 receptor and cellular responses. Evidence and counterevidence regarding this canonical pathway require closer look at the covariates so that the incredible potential of KISS1 can be realized.
    Keywords:  Dormancy; G protein-coupled receptor; KISS1; KISS1R; Metastasis; Metastasis suppressor
    DOI:  https://doi.org/10.1007/s10555-020-09868-9
  7. Cell. 2020 Mar 09. pii: S0092-8674(20)30219-1. [Epub ahead of print]
    Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
    Samir Devalaraja, Tsun Ki Jerrick To, Ian W Folkert, Ramakrishnan Natesan, Md Zahidul Alam, Minghong Li, Yuma Tada, Konstantin Budagyan, Mai T Dang, Li Zhai, Graham P Lobel, Gabrielle E Ciotti, T S Karin Eisinger-Mathason, Irfan A Asangani, Kristy Weber, M Celeste Simon, Malay Haldar.
      The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we find that the TME induces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocyte differentiation toward TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade. Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple human tumors. RA has been considered as an anti-cancer agent, whereas our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
    Keywords:  dendritic cell; immune checkpoint blockade; immune evasion; macrophage; monocyte; retinoic acid; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2020.02.042
  8. Cancer Metab. 2020 ;8 4
    Glutaminase-1 (GLS1) inhibition limits metastatic progression in osteosarcoma.
    L Ren, V Ruiz-Rodado, T Dowdy, S Huang, S H Issaq, J Beck, H Wang, C Tran Hoang, A Lita, M Larion, A K LeBlanc.
       Background: Osteosarcoma (OS) is a malignant bone tumor that often develops during the period of rapid growth associated with adolescence. Despite successful primary tumor control accompanied by adjuvant chemotherapy, death from pulmonary metastases occurs in approximately 30% of patients within 5 years. As overall survival in patients remains unchanged over the last 30 years, urgent needs for novel therapeutic strategies exist. Cancer metastasis is characterized by complex molecular events which result from alterations in gene and protein expression/function. Recent studies suggest that metabolic adaptations, or "metabolic reprogramming," may similarly contribute to cancer metastasis. The goal of this study was to specifically interrogate the metabolic vulnerabilities of highly metastatic OS cell lines in a series of in vitro and in vivo experiments, in order to identify a tractable metabolically targeted therapeutic strategy for patients.
    Methods: Nutrient deprivation and drug treatment experiments were performed in MG63.3, 143B, and K7M2 OS cell lines to identify the impact of glutaminase-1 (GLS1) inhibition and metformin treatment on cell proliferation. We functionally validated the impact of drug treatment with extracellular flux analysis, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. 13C-glucose and 13C-glutamine tracing was employed to identify specific contributions of these nutrients to the global metabolic profiles generated with GLS1 inhibition and metformin treatment in vivo.
    Results: Highly metastatic OS cell lines require glutamine for proliferation, and exposure to CB-839, in combination with metformin, induces both primary tumor growth inhibition and a distinct reduction in metastatic outgrowth in vivo. Further, combination-treated OS cells showed a reduction in cellular mitochondrial respiration, while NMR confirmed the pharmacodynamic effects of glutaminase inhibition in tumor tissues. We observed global decreases in glycolysis and tricarboxylic acid (TCA) cycle functionality, alongside an increase in fatty acid oxidation and pyrimidine catabolism.
    Conclusions: This data suggests combination-treated cells cannot compensate for metformin-induced electron transport chain inhibition by upregulating glutaminolysis to generate TCA cycle intermediates required for cell proliferation, translating into significant reductions in tumor growth and metastatic progression. This therapeutic approach could be considered for future clinical development for OS patients presenting with or at high risk of developing metastasis.
    Keywords:  Glutaminase; Metabolism; Metastasis; Metformin; Osteosarcoma
    DOI:  https://doi.org/10.1186/s40170-020-0209-8
  9. Oncogene. 2020 Mar 10.
    Feedback analysis identifies a combination target for overcoming adaptive resistance to targeted cancer therapy.
    Sang-Min Park, Chae Young Hwang, Jihye Choi, Chang Young Joung, Kwang-Hyun Cho.
      Targeted drugs aim to treat cancer by directly inhibiting oncogene activity or oncogenic pathways, but drug resistance frequently emerges. Due to the intricate dynamics of cancer signaling networks, which contain complex feedback regulations, cancer cells can rewire these networks to adapt to and counter the cytotoxic effects of a drug, thereby limiting the efficacy of targeted therapies. To identify a combinatorial drug target that can overcome such a limitation, we developed a Boolean network simulation and analysis framework and applied this approach to a large-scale signaling network of colorectal cancer with integrated genomic information. We discovered Src as a critical combination drug target that can overcome the adaptive resistance to the targeted inhibition of mitogen-activated protein kinase pathway by blocking the essential feedback regulation responsible for resistance. The proposed framework is generic and can be widely used to identify drug targets that can overcome adaptive resistance to targeted therapies.
    DOI:  https://doi.org/10.1038/s41388-020-1255-y
  10. Nat Commun. 2020 Mar 09. 11(1): 1280
    Minimal barriers to invasion during human colorectal tumor growth.
    Marc D Ryser, Diego Mallo, Allison Hall, Timothy Hardman, Lorraine M King, Sergei Tatishchev, Inmaculada C Sorribes, Carlo C Maley, Jeffrey R Marks, E Shelley Hwang, Darryl Shibata.
      Intra-tumoral heterogeneity (ITH) could represent clonal evolution where subclones with greater fitness confer more malignant phenotypes and invasion constitutes an evolutionary bottleneck. Alternatively, ITH could represent branching evolution with invasion of multiple subclones. The two models respectively predict a hierarchy of subclones arranged by phenotype, or multiple subclones with shared phenotypes. We delineate these modes of invasion by merging ancestral, topographic, and phenotypic information from 12 human colorectal tumors (11 carcinomas, 1 adenoma) obtained through saturation microdissection of 325 small tumor regions. The majority of subclones (29/46, 60%) share superficial and invasive phenotypes. Of 11 carcinomas, 9 show evidence of multiclonal invasion, and invasive and metastatic subclones arise early along the ancestral trees. Early multiclonal invasion in the majority of these tumors indicates the expansion of co-evolving subclones with similar malignant potential in absence of late bottlenecks and suggests that barriers to invasion are minimal during colorectal cancer growth.
    DOI:  https://doi.org/10.1038/s41467-020-14908-7
  11. Cancer Res. 2020 Mar 10. pii: canres.2235.2019. [Epub ahead of print]
    IL33 is a key driver of treatment resistance of cancer.
    Chie Kudo-Saito, Takahiro Miyamoto, Hiroshi Imazeki, Hirokazu Shoji, Kazunori Aoki, Narikazu Boku.
      Recurrence and treatment resistance are major causes of cancer-associated death. There has been a growing interest in better understanding epithelial-mesenchymal transition (EMT), stemness of cancer cells, and exhaustion and dysfunction of the immune system for which numerous genomic, proteomic, microenvironmental, and immunological mechanisms have been demonstrated. However, practical treatments for such patients have not yet been established. Here we identified interleukin-33 (IL33) as a key driver of polyploidy followed by rapid proliferation after treatment. IL33 induction transformed tumor cells into polyploid giant cells, showing abnormal cell cycle without cell division accompanied by Snail deregulation and p53 inactivation; small progeny cells were generated in response to treatment stress. Simultaneously, soluble IL33 was released from tumor cells, leading to expansion of receptor ST2-expressing cells including IL17RB+GATA3+ cells, which promoted tumor progression and metastasis directly and indirectly via induction of immune exhaustion and dysfunction. Blocking IL33 with a specific mAb in murine IL33+ metastatic tumor models abrogated negative consequences and successfully elicited anti-tumor efficacy induced by other combined treatments. Ex vivo assays using tumor tissues and PBMCs of cancer patients validated the clinical relevancy of these findings. Together, these data suggest that targeting the IL33-ST2 axis is a promising strategy for diagnosis and treatment of patients likely to be resistant to treatments in the clinical setting.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2235
  12. Clin Cancer Res. 2020 Mar 13. pii: clincanres.3005.2019. [Epub ahead of print]
    Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer.
    Heather A Parsons, Justin Rhoades, Sarah C Reed, Greg Gydush, Priyanka Ram, Pedro Exman, Kan Xiong, Christopher C Lo, Tianyu Li, Mark Fleharty, Gregory J Kirkner, Denisse Rotem, Ofir Cohen, Fangyan Yu, Mariana Fitarelli-Kiehl, Ka Wai Leong, Melissa E Hughes, Shoshana M Rosenberg, Laura C Collins, Kathy D Miller, Brendan Blumenstiel, Lorenzo Trippa, Carrie Cibulskis, Donna S Neuberg, Matthew DeFelice, Samuel S Freeman, Niall J Lennon, Nikhil Wagle, Gavin Ha, Daniel G Stover, Atish D Choudhury, Gad Getz, Eric P Winer, Matthew Meyerson, Nancy U Lin, Ian Krop, J Christopher Love, G Mike Makrigiorgos, Ann H Partridge, Erica L Mayer, Todd R Golub, Viktor Adalsteinsson.
       PURPOSE: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1000-fold lower error rate than conventional sequencing.
    EXPERIMENTAL DESIGN: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within six months following metastatic diagnosis and 142 patients with stage 0-III breast cancer who received curative-intent treatment with most sampled at surgery and one year post-op. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.
    RESULTS: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median 57, range 2-346). Clinical sensitivity was 81% (n=13/16) in newly diagnosed MBC, 23% (n=7/30) at post-op and 19% (n=6/32) at one year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at one year was strongly associated with distant recurrence (HR=20.8 [95%CI: 7.3-58.9]). Median lead time from first positive sample to recurrence was 18.9 months (range: 3.4-39.2 months).
    CONCLUSIONS: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-3005
  13. FASEB J. 2020 Mar 10.
    Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2α drives metastasis of hepatocellular carcinoma.
    Man-Qing Cao, A-Bin You, Wei Cui, Su Zhang, Zhi-Gui Guo, Lu Chen, Xiao-Dong Zhu, Wei Zhang, Xiao-Lin Zhu, Hua Guo, Da-Jun Deng, Hui-Chuan Sun, Ti Zhang.
      Oxidative stress and hypoxia are two opposite microenvironments involved in HCC metastasis. Thioredoxin (TXN) and hypoxia-inducible factor 2α (HIF-2α) are typical proteins involved in these two different microenvironments, respectively. How these two factors interact to influence the fate on tumor cells remains unknown. Hypoxia facilitated HCC cells withstood oxidative stress and eventually promoted HCC cells metastasis, in which TXN and HIF-2α were mostly involved. Upregulation of TXN/HIF-2α correlated with poor HCC prognosis and promoted HCC metastasis both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) process was involved in TXN/HIF-2α-enhanced invasiveness of HCC cells. Additionally, the stability and activity of HIF-2α were precisely regulated by TXN via SUMOylation and acetylation, which contributed to HCC metastasis. Our data revealed that the redox protein TXN and HIF-2α are both associated with HCC metastasis, and the fine regulation of TXN on HIF-2α contributes essentially during the process of metastasis. Our study provides new insight into the interaction mechanism between hypoxia and oxidative stress and implies potential therapeutic benefits by targeting both TXN and HIF-2α in the treatment of HCC metastasis.
    Keywords:  HIF-2α; hepatocellular carcinoma; metastasis; thioredoxin
    DOI:  https://doi.org/10.1096/fj.202000082R
  14. Cancer Discov. 2020 Mar 13.
    Gastrin Blocks Symmetric Stem-Cell Division and Gastric Tumorigenesis.
      Symmetric division of stem cells positive for gastrin receptor CCK2R is linked to gastric cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-038
  15. Nat Commun. 2020 Mar 12. 11(1): 1335
    Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours.
    Ellen Brenner, Barbara F Schörg, Fatima Ahmetlić, Thomas Wieder, Franz Joachim Hilke, Nadine Simon, Christopher Schroeder, German Demidov, Tanja Riedel, Birgit Fehrenbacher, Martin Schaller, Andrea Forschner, Thomas Eigentler, Heike Niessner, Tobias Sinnberg, Katharina S Böhm, Nadine Hömberg, Heidi Braumüller, Daniel Dauch, Stefan Zwirner, Lars Zender, Dominik Sonanini, Albert Geishauser, Jürgen Bauer, Martin Eichner, Katja J Jarick, Andreas Beilhack, Saskia Biskup, Dennis Döcker, Dirk Schadendorf, Leticia Quintanilla-Martinez, Bernd J Pichler, Manfred Kneilling, Ralph Mocikat, Martin Röcken.
      Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.
    DOI:  https://doi.org/10.1038/s41467-020-14987-6
  16. Elife. 2020 Mar 10. pii: e51373. [Epub ahead of print]9
    PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells.
    Payal Jain, Cecilia Ballare, Enrique Blanco, Pedro Vizan, Luciano Di Croce.
      The Polycomb-like protein PHF19/PCL3 associates with PRC2 and mediates its recruitment to chromatin in embryonic stem cells. PHF19 is also overexpressed in many cancers. However, neither PHF19 targets nor misregulated pathways involving PHF19 are known. Here, we investigate the role of PHF19 in prostate cancer cells. We find that PHF19 interacts with PRC2 and binds to PRC2 targets on chromatin. PHF19 target genes are involved in proliferation, differentiation, angiogenesis, and extracellular matrix organization. Depletion of PHF19 triggers an increase in MTF2/PCL2 chromatin recruitment, with a genome-wide gain in PRC2 occupancy and H3K27me3 deposition. Transcriptome analysis shows that PHF19 loss promotes deregulation of key genes involved in growth, metastasis, invasion, and of factors that stimulate blood vessels formation. Consistent with this, PHF19 silencing reduces cell proliferation, while promotes invasive growth and angiogenesis. Our findings reveal a role for PHF19 in controlling the balance between cell proliferation and invasiveness in prostate cancer.
    Keywords:  Polycomb; chromosomes; gene expression; human; phf19; prostate cancer
    DOI:  https://doi.org/10.7554/eLife.51373
  17. Nat Rev Clin Oncol. 2020 Mar 09.
    Lineage plasticity in cancer: a shared pathway of therapeutic resistance.
    Álvaro Quintanal-Villalonga, Joseph M Chan, Helena A Yu, Dana Pe'er, Charles L Sawyers, Sen Triparna, Charles M Rudin.
      Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer - the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives - was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.
    DOI:  https://doi.org/10.1038/s41571-020-0340-z
  18. Nature. 2020 03;579(7798): 196-197
    Tweaking the DNA of myeloid cells curbs cancer spread.
    Ali Ghasemi, Michele De Palma.
      
    Keywords:  Cancer; Epigenetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-020-00481-y
  19. Biomaterials. 2020 Feb 28. pii: S0142-9612(20)30169-1. [Epub ahead of print]242 119923
    Ru@CeO2 yolk shell nanozymes: Oxygen supply in situ enhanced dual chemotherapy combined with photothermal therapy for orthotopic/subcutaneous colorectal cancer.
    Xufeng Zhu, Youcong Gong, Yanan Liu, Chunhua Yang, Sijie Wu, Guanglong Yuan, Xian Guo, Jie Liu, Xiuying Qin.
      Hypoxia is an important factor in forming multidrug resistance, recurrence and metastasis in solid tumors. Nanozymes respond to tumor microenvironment for tumor-specific treatment is a new and effective strategy. In this study, one-pot method was used to synthesize hollow Ru@CeO2 yolk shell nanozymes (Ru@CeO2 YSNs), which possess excellent light-to-heat conversion efficiency and catalytic performance. Antitumor drug ruthenium complex (RBT) and resveratrol (Res) were dual-loaded in Ru@CeO2 YSNs, and a double outer layer structure using polyethylene glycol was constructed to form dual-drug delivery system (Ru@CeO2-RBT/Res-DPEG) that was released on demand. The double outer layer structure increased the biocompatibility of Ru@CeO2 YSNs and effectively prolong the circulation time in blood. Ru@CeO2-RBT/Res-DPEG catalyzes endogenous H2O2 to produce oxygen, which achieve in situ oxygen supply and enhanced dual-chemotherapy and photothermal therapy (PTT) for colorectal cancer. In vitro studies found that Ru@CeO2-RBT/Res-DPEG has good tumor penetration depth and antitumor effect. In addition, Ru@CeO2-RBT/Res-DPEG can alleviate tumor hypoxia, and inhibit metastasis and recurrence of orthotopic and subcutaneous colorectal cancer. Accordingly, the study shows that yolk shell nanozymes can be used as an efficient synergistic system for dual-chemotherapy and PTT to kill tumor and inhibit orthotopic colorectal cancer metastasis and recurrence.
    Keywords:  Colorectal cancer; Dual-chemotherapy; Metastasis; Photothermal therapy; Tumor hypoxia
    DOI:  https://doi.org/10.1016/j.biomaterials.2020.119923
  20. BMJ. 2020 Mar 10. 368 m770
    Inappropriate use of progression-free survival in cancer drug approvals.
    Huseyin Naci, Courtney Davis.
      
    DOI:  https://doi.org/10.1136/bmj.m770
  21. Nat Rev Cancer. 2020 Mar 11.
    Inflammatory microenvironment remodelling by tumour cells after radiotherapy.
    Martin McLaughlin, Emmanuel C Patin, Malin Pedersen, Anna Wilkins, Magnus T Dillon, Alan A Melcher, Kevin J Harrington.
      The development of immune checkpoint inhibitors (ICIs) is revolutionizing the way we think about cancer treatment. Even so, for most types of cancer, only a minority of patients currently benefit from ICI therapies. Intrinsic and acquired resistance to ICIs has focused research towards new combination therapy approaches that seek to increase response rates, the depth of remission and the durability of benefit. In this Review, we describe how radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs. We describe how recent research on DNA damage response (DDR) inhibitors in combination with radiotherapy may be used to augment this approach. Radiotherapy can kill cancer cells while simultaneously triggering the release of pro-inflammatory mediators and increasing tumour-infiltrating immune cells - phenomena often described colloquially as turning immunologically 'cold' tumours 'hot'. Here, we focus on new developments illustrating the key role of tumour cell-autonomous signalling after radiotherapy. Radiotherapy-induced tumour cell micronuclei activate cytosolic nucleic acid sensor pathways, such as cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), and propagation of the resulting inflammatory signals remodels the immune contexture of the tumour microenvironment. In parallel, radiation can impact immunosurveillance by modulating neoantigen expression. Finally, we highlight how tumour cell-autonomous mechanisms might be exploited by combining DDR inhibitors, ICIs and radiotherapy.
    DOI:  https://doi.org/10.1038/s41568-020-0246-1
  22. Nat Commun. 2020 Mar 09. 11(1): 1265
    Time-lapse single-cell transcriptomics reveals modulation of histone H3 for dormancy breaking in fission yeast.
    Hayato Tsuyuzaki, Masahito Hosokawa, Koji Arikawa, Takuya Yoda, Naoyuki Okada, Haruko Takeyama, Masamitsu Sato.
      How quiescent cells break dormancy is a key issue in eukaryotic cells including cancer. Fungal spores, for example, remain quiescent for long periods until nourished, although the mechanisms by which dormancy is broken remain enigmatic. Transcriptome analysis could provide a clue, but methods to synchronously germinate large numbers of spores are lacking, and thus it remains a challenge to analyse gene expression upon germination. Hence, we develop methods to assemble transcriptomes from individual, asynchronous spore cells of fission yeast undergoing germination to assess transcriptomic changes over time. The virtual time-lapse analyses highlights one of three copies of histone H3 genes whose transcription fluctuates during the initial stage of germination. Disruption of this temporal fluctuation causes defects in spore germination despite no visible defects in other stages of the life cycle. We conclude that modulation of histone H3 expression is a crucial 'wake-up' trigger at dormancy breaking.
    DOI:  https://doi.org/10.1038/s41467-020-15060-y
  23. Mol Cancer. 2020 Mar 12. 19(1): 54
    Long non-coding RNAs regulate drug resistance in cancer.
    Kaisheng Liu, Lin Gao, Xiaoshi Ma, Juan-Juan Huang, Juan Chen, Leli Zeng, Charles R Ashby, Chang Zou, Zhe-Sheng Chen.
      Chemoresistance, whether intrinsic or acquired, is a major obstacle in the treatment of cancer. The resistance of cancer cells to chemotherapeutic drugs can result from various mechanisms. Over the last decade, it has been reported that 1ong noncoding RNAs (lncRNAs) can mediate carcinogenesis and drug resistance/sensitivity in cancer cells. This article reviews, in detail, recent studies regarding the roles of lncRNAs in mediating drug resistance.
    Keywords:  Cancer; Drug resistance; Long non-coding RNAs
    DOI:  https://doi.org/10.1186/s12943-020-01162-0
  24. Drug Resist Updat. 2020 Feb 25. pii: S1368-7646(20)30010-8. [Epub ahead of print]50 100683
    Long non-coding RNAs as a determinant of cancer drug resistance: Towards the overcoming of chemoresistance via modulation of lncRNAs.
    Wenxiao Jiang, Jun Xia, Shangdan Xie, Ruanmin Zou, Shuya Pan, Zhi-Wei Wang, Yehuda G Assaraf, Xueqiong Zhu.
      Chemoresistance including intrinsic and acquired anticancer drug resistance continues to be a primary hindrance towards curative cancer treatment. Therefore, deciphering the underlying molecular mechanisms is of paramount importance required towards the overcoming of chemoresistance. Cumulative evidence revealed that long non-coding RNAs (lncRNAs) play a pivotal role in conferring anticancer drug resistance upon a broad spectrum of cancers. Hence, numerous lncRNAs are recognized as novel biomarkers and therapeutic targets in the diagnosis and treatment of malignancies, which urges us to comprehensively delineate the critical functions of lncRNAs in chemoresistance. In this respect, we herein succinctly elucidate the molecular mechanisms by which lncRNAs modulate their downstream targets to mediate cancer chemoresistance. Therefore, the current review may provide a significant basis for the future conquering of chemoresistance via targeting lncRNAs in cancer therapeutics.
    Keywords:  Cancer; Chemotherapy; Drug resistance; Long non-coding RNA; Pathway; Target; miRNA
    DOI:  https://doi.org/10.1016/j.drup.2020.100683
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