Top 10 Challenges in Cancer Immunotherapy

Immunity, Journal Year: 2020, Volume and Issue: 52(1), P. 17 - 35

Published: Jan. 1, 2020

Language: Английский

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Modeling neoplastic disease with spheroids and organoids

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: July 16, 2020

Abstract Cancer is a complex disease in which both genetic defects and microenvironmental components contribute to the development, progression, metastasization of disease, representing major hurdles identification more effective safer treatment regimens for patients. Three-dimensional (3D) models are changing paradigm preclinical cancer research as they closely resemble tissue environment architecture found clinical tumors than bidimensional (2D) cell cultures. Among 3D models, spheroids organoids represent most versatile promising that capable recapitulating heterogeneity pathophysiology human cancers filling gap between conventional 2D vitro testing animal models. Such systems powerful tool studying biology, enabling us model dynamic evolution neoplastic from early stages metastatic dissemination interactions with microenvironment. Spheroids have recently been used field drug discovery personalized medicine. The combined use could potentially improve robustness reliability data, reducing need favoring their transition practice. In this review, we summarize recent advances these modeling, focusing on innovative translational applications, looking at future challenges, comparing them widely

Language: Английский

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The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors

Materials, Journal Year: 2019, Volume and Issue: 12(18), P. 2945 - 2945

Published: Sept. 11, 2019

The ideal in vitro recreation of the micro-tumor niche—although much needed for a better understanding cancer etiology and development anticancer therapies—is highly challenging. Tumors are complex three-dimensional (3D) tissues that establish dynamic cross-talk with surrounding through chemical signaling. An extensive body experimental evidence has established 3D culture systems more closely recapitulate architecture physiology human solid tumors when compared traditional 2D systems. Moreover, conventional fail to recreate dynamics tumor niche. Tumor-on-chip systems, which microfluidic devices aim relevant features physiology, have recently emerged as powerful tools research. In tumor-on-chip use microfluidics adds another dimension physiological mimicry by allowing continuous feed nutrients (and pharmaceutical compounds). Here, we discuss published literature related tumor-like (tumor-on-chip devices). Our is provide readers an overview state art on this particular theme illustrate toolbox available today engineering structures their environments) devices. suitability increasing many areas research, including study tumors, screening novel compounds before resourcing animal models, personalized treatments. years come, additive manufacturing (3D bioprinting printing), computational fluid dynamics, medium- high-throughput omics will become enablers new wave sophisticated effective

Language: Английский

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Strategies for 3D bioprinting of spheroids: A comprehensive review

Biomaterials, Journal Year: 2022, Volume and Issue: 291, P. 121881 - 121881

Published: Oct. 27, 2022

Language: Английский

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Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment

Biomedicines, Journal Year: 2023, Volume and Issue: 11(4), P. 1058 - 1058

Published: March 30, 2023

In the last decades three-dimensional (3D) in vitro cancer models have been proposed as a bridge between bidimensional (2D) cell cultures and vivo animal models, gold standards preclinical assessment of anticancer drug efficacy. 3D can be generated through multitude techniques, from both immortalized lines primary patient-derived tumor tissue. Among them, spheroids organoids represent most versatile promising they faithfully recapitulate complexity heterogeneity human cancers. Although their recent applications include screening programs personalized medicine, not yet established tools for studying efficacy supporting preclinical-to-clinical translation, which remains mainly based on experimentation. this review, we describe state-of-the-art evaluation agents, focusing potential contribution to replace, reduce refine experimentations, highlighting strength weakness, discussing possible perspectives overcome current challenges.

Language: Английский

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RASSF 1A controls tissue stiffness and cancer stem‐like cells in lung adenocarcinoma

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(13)

Published: May 27, 2019

Article27 May 2019Open Access Source Data RASSF1A controls tissue stiffness and cancer stem-like cells in lung adenocarcinoma Daniela Pankova Department of Oncology, University Oxford, UK Search for more papers by this author Yanyan Jiang Oxford Institute Radiation Maria Chatzifrangkeskou orcid.org/0000-0003-3703-491X Iolanda Vendrell TDI Mass Spectrometry Laboratory, Nuffield Medicine, Target Discovery Jon Buzzelli Anderson Ryan Cameron Brown School Chemistry, Physics Mechanical Engineering, Queensland Technology, Brisbane, Qld, Australia Eric O'Neill Corresponding Author [email protected] orcid.org/0000-0002-0060-6278 Systems Biology Ireland, College Dublin, Dublin 4, Ireland Information Pankova1, Jiang1,2, Chatzifrangkeskou1, Vendrell1,3, Buzzelli1, Ryan1,2, Brown4 *,1,5 1Department 2Oxford 3TDI 4School 5Systems *Corresponding author. Tel: +44 1865617321; E-mail: The EMBO Journal (2019)38:e100532https://doi.org/10.15252/embj.2018100532 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision process including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Lung remains leading cause cancer-related death due poor treatment resistance arising from tumour heterogeneity. Here, we show that adverse prognosis associated with epigenetic silencing suppressor is increased deposition extracellular matrix (ECM), metastatic dissemination vitro vivo. We find promoter methylation display constitutive nuclear YAP1 accumulation expression prolyl 4-hydroxylase alpha-2 (P4HA2) which increases collagen deposition. Furthermore, identify elevated creates stiff ECM turn triggers programming Re-expression or inhibition P4HA2 activity reverses these effects markers differentiation (TTF-1 Mucin 5B). Our study identifies as clinical biomarker mechanical properties levels stemness risk progression adenocarcinoma. Moreover, highlight potential target uncoupling signals support stemness. Synopsis hippo signaling regulator established tumor solid cancers, but vivo consequences its loss have been difficult discern. This finds suppression promote YAP-dependent deposition, stiffness, stem-cell reprograming, metastasis. suppresses Loss leads hydroxylase (ECM) stiffness. overrides RASSF1A-mediated restriction oncogenic YAP transcription. High emergence cells. Introduction Cellular heterogeneity within microenvironment has reported general property cancers (Hanahan Weinberg, 2011; Marusyk et al, 2014). population referred stem (CSCs) exhibit extensive self-renewal abilities, multi-potent formation (Al-Hajj 2003; Ponti 2005; Sales 2007; Wang 2013). Although CSCs represent < 1% total tumour, they major contributing factor radio conventional chemotherapy aggressive (Salcido 2010; Kaseb 2016). Dedifferentiation pluripotent-like state results appearance during malignant tumorigenesis (Codony-Servat 2016); however, mechanism behind tumours be elucidated. Evidence suggests interaction surrounding microenvironmental niche contributes conversion non-stem (Chaffer Gupta 2011). Both biochemical physical can modulate endowing them adapt emerging (Chen 2012; Driessens Schepers Schwitalla provided e.g. enhanced crosslinking, described influence CSC plasticity trigger (Wong Rustgi, 2013; Ye In line promotion CSCs, also correlates invasion, migration spreading (Morrison Spradling, 2008; Lane 2014; Scadden, Turner Dalby, Mechanotransduction serves upstream Hippo pathway transcription factors YAP/TAZ (Piccolo 2014), recently an essential component (Halder Johnson, Tremblay Camargo, Park 2018). Nuclear responsible numerous restricted pathway-mediated phosphorylation on serine127 (YAP1-pS127) (Zhao Zanconato 2015). key signalling humans, correlated reduced YAP1-pS127 across multiple cohorts, (Vlahov Independently, extensively validated where methylation-associated gene overall survival (Burbee 2001; Lee Neyaz Pallarés Grawenda O'Neill, studied vitro, precise consequence Gene analysis breast insight as, addition activation, embryonic cell (ESC) signatures are significantly human lacking (Pefani To address loss, directly assessed characteristics orthotopic model found impedes growth dissemination. demonstrated driven supports I Concomitantly, high elevation negatively our data indicate induces pluripotency cassette (NANOG, OCT4 SOX2) via β-catenin-YAP-associated transcription, null Interestingly, itself may potentially mechanoresponsive only soft ECM, fails do so ECM. Together, provides evidence widespread prognostic value attributed remodelling occurrence CSCs. These findings offer clearer information RASSF1 new therapeutic opportunities combat underlying failures. Results DNA CpG island spanning widely appreciated associate outcome non-small (Kim Fischer 2007). Surprisingly, similar association mRNA lacking. this, explored patients Cancer Genome Atlas (TCGA) positively good not squamous carcinomas (Fig 1A). physiological role involvement progression, constructed isogenic H1299 lines (where highly methylated) transfected either pcDNA3, H1299control, stably expressing RASSF1A, H1299RASSF1A 1B). As one central scaffolds mammalian (Matallanas 2007), higher LATS1-pS909 cells, signifying kinase activated presence Proliferation assays maintains intrinsic proliferation rates H1299control 1B, graph) therefore serve appropriate system RASSF1A-specific determine employed accurately recapitulate natural microenvironment, asses relationship between biological allow monitoring primary site 1C) (Boehle 2000). Orthotopic mouse injection was performed intrathoracic avoid pneumothorax damage previously (Onn Servais 2012). were injected into left mice examined events after 17 30 days (Figs 1D E, EV1A B, Table EV1). Metastatic counted quantified surface nodules euthanized, 2015; Tan At day 30, 13/14 two different experiments separate pools (in expressed) developed clear lungs EV1A). ipsilateral (left lung) metastases 12/14 contralateral right 1E, 8/12 tumours, there striking both (left) (right) at EV1A, suggest minor suppressive effect growth, significant events. When sacrificed earlier (day 17), no difference apparent time, suggesting unlikely early event mature EV1B). Primary accompanied production liquid oedema (Movies EV1 EV2) around indicating possible inflammation (Matthay, 2014); staining macrophage marker F4/80 indicated inflammatory response EV1C). next selected HOP92 express endogenous 2016) comparable derivative shRASSF1A silence expression. Inactivation confirmed HOP92shRASSF1A EV1D), and, contrast rate EV1D). HOP92shcontrol resulted limited (1/7 mice, 16%), upon (3/7 42%) least EV1E, EV2). Taken together, imply most likely Figure 1. metastasis Kaplan–Meier curves (OS) TCGA_LUAD (RASSF1 high/low cutoff FKPM 5.85) carcinoma TCGA_LUSC 6.52). Significance derived log-rank test. Western blot antibodies empty vector pcDNA3 (H1299control) (H1299RASSF1A). Bottom: resazurin assay. (n = 2). Error bars mean ± SEM. Cartoon injection, sites (ipsil ipsilateral, same tumour; contra opposite lung). Mice euthanized collect inoculation lung. Size measured 14 per group; experimental groups 6 8 shading represents independent experiments) re-expressing 12 6). size MRI software ITK-SNAP. Statistical significance 2-tailed Student's t-test. Visual assessment quantification lungs, generated 30. Result calculated (as D). Graph shows decreasing when H1299RASSF1A. available online figure. 1 [embj2018100532-sup-0007-SDataFig1.pdf] Download figure PowerPoint Click here expand EV1. Representative longitudinal MR images individual formed overexpressed Red arrowheads lungs. Bottom panel: macroscopic appearances identified patchy whitish areas. arrows 4 group). fluorescence stained macrophages (green) DAPI (blue). Images presented merge DAPI. Scale bars: 100 μm. analyses pYAP1 protein stable knockdown shRNA lentiviral transfection. Right: Resazurin assay used analysing ratio great impaired. using t-test 2-(tailed) n 2 experiments, error Left: showing Knockdown (shRASSF1A) 7 group) ability bear control group, expressed (shcontrol) injection. Invasion autonomous involves cross-talk stromal (Xu 2009). absence appears development; therefore, hypothesized distinct. candidates involved, mass spectrometry isolated expected, variety components produced collagens, laminins fibronectin; exclusively contained trophoblast glycoprotein (TPBG), laminin-beta2 (LAMB2), (P4HA2), ADAMTSL5 SERPINB9 2A). correlate low 2B). Reciprocally, MRX7A, SDF2, TFPI2 TIMP1 specifically which, conversely above, 2B) EV2A). enzyme involved collagen-specific posttranslational modification, catalysing 4-hydroxyproline residues, crucial proper folding fibre stabilization (Myllyharju, 2003, 2008). further evaluated TCGA worse clinicopathological many EV2B). Immunohistochemical (IHC) (peri-nuclear localization processing ER; Human Protein Atlas), 2C). ascertain if functional consequence, first enrichment hydroxyproline 2D). fibres, concomitantly, observed compared H1299RASSF1A(Fig 2E), known hydroxyprolinated (Mizuno 2004). evaluate whether activity, immunofluorescence (IF) siRNA targeting inhibitor 1,4-DihydroPhenonthrolin-Carboxylic Acid (DPCA) restrict 2E–G). dependent P4HA2; moreover, lack additive siP4HA2 plus DPCA working through 2G). collagen, mRNA, transcriptional reason EV2C stimulated IF induced (Fig. 2H I). additional control, suppressed HeLa induction 2J). 2. proteins purified results. Only peptides taken consideration. resulting list 3). plots depicting (lung adenocarcinoma) revealed proteomics. H&E IHC P4HA2, (bars) regions 5 3 tumours. Hydroxyproline (Cell biolabs Inc.) (4 μM) (DPCA), against combination. Quantification negative comparison. Fig EV2C. Immunofluorescence (right RASSF1A. 20 information: Unless otherwise indicated, all statistical (two-tailed) [embj2018100532-sup-0008-SDataFig2.pdf] EV2. Expression proteomics extracted better prognosis. P values Clinical percentage various versus P4HA2. collected TCGA. intensity without knockdown, 1.4DPCA combination both. graph: Treatment siRNAP4HA2, P4HA 1.4-DPCA (inh.) decreased 10 RT–PCR relative validating knockdown. alters invasion related alterations investigated invasive altered H1299control. RASSF1A-expressing invade three-dimensional (3D) 3A). However, since complex mimics parenchymal (Liotta, 1986), additionally Matrigel matrix, enriched laminins, investigate depletion basement membrane. equivalent level 3B). hypothesis, tested 3C). Tissue alignment processes facilitate surrounded (Miron-Mendoza Gehler Han stability, gel contraction assesses reorganize 3D-collagen vitro. After days, plugs apparent, whereas containing remained unaltered 3D). impaired blocking 3D), invasion. how respond spheroids embedded 3E). sensor regulated activate Taz Dupont Piersma strong 3D spheroids, whereas, (Ueno Papageorgis 2015)with observe 3F). led us question activation result adoptive decellularized (control ECM) alone sufficient re-seeded Re-seeding onto their own did affect localization, interestingly predominantly cytoplasmic became concentrated nucleus plated 3G). order test reducing c

Language: Английский

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AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 217(10)

Published: Aug. 4, 2020

Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack animal models that faithfully recapitulate different subtypes impedes adequate preclinical testing stratified therapeutic concepts. Here, we demonstrate constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with carcinogen azoxymethane. Gene-expression profiling indicates Trp53ΔIECAktE17K tumors resemble human mesenchymal (CMS4), is characterized by poorest survival rate among four CMSs. are Notch3 up-regulation, treatment NOTCH3-inhibiting antibody reduces metastasis. In patients, NOTCH3 expression correlates positively grading presence lymph node as well distant metastases specifically up-regulated CMS4 tumors. Therefore, suggest putative target for advanced patients.

Language: Английский

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AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 30, 2024

Due to low success rates and long cycles of traditional drug development, the clinical tendency is apply omics techniques reveal patient-level disease characteristics individualized responses treatment. However, heterogeneous form data uneven distribution targets make discovery precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as paradigm uses mining large TNBC cohort databases establish biofactor-regulated neural network rapidly screening optimizing compound pairs. Subsequently, biomimetic nanococrystals are prepared using preferred combination mitoxantrone gambogic acid rational delivery. The unique mechanism obtained regulating genes through ribosomal stress triggering cascade immune effects revealed in models. In this work, target omics-based intelligent framework explores an innovative development paradigm, which repurposes existing drugs enables precise treatment refractory diseases.

Language: Английский

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Application of Real-World Data to External Control Groups in Oncology Clinical Trial Drug Development

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 11

Published: Jan. 6, 2022

Randomized controlled trials (RCTs) that assess overall survival are considered the “gold standard” when evaluating efficacy and safety of a new oncology intervention. However, single-arm use surrogate endpoints (e.g., objective response rate or duration response) to evaluate clinical benefit have become basis for accelerated breakthrough regulatory approval precision drugs cases where target research populations relatively small. Interpretation in can be challenging because such studies lack standard-of-care comparator arm. Although an external control group based on data from other trials, using collected outside trial may not only offer alternative both RCTs uncontrolled but it also help improve decision-making by study sponsors authorities. Hence, leveraging real-world (RWD) construct arms investigate drug interventions has topic interest. Herein, we review benefits challenges associated with RWD groups, relevance early development.

Language: Английский

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Reconstructing the tumor architecture into organoids

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 176, P. 113839 - 113839

Published: June 19, 2021

Language: Английский

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