Overcoming Endocrine Resistance in Breast Cancer

Cancer Cell, Journal Year: 2020, Volume and Issue: 37(4), P. 496 - 513

Published: April 1, 2020

Language: Английский

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Autophagy and autophagy-related pathways in cancer

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(8), P. 560 - 575

Published: March 2, 2023

Language: Английский

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Lactate metabolism in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 1, 2022

Abstract The current understanding of lactate extends from its origins as a byproduct glycolysis to role in tumor metabolism, identified by studies on the Warburg effect. shuttle hypothesis suggests that plays an important bridging signaling molecule coordinates among different cells, organs and tissues. Lactylation is posttranslational modification initially reported Professor Yingming Zhao’s research group 2019. Subsequent confirmed lactylation vital component function involved proliferation, neural excitation, inflammation other biological processes. An indispensable substance for various physiological cellular functions, regulatory aspects energy metabolism signal transduction. Therefore, comprehensive review summary presented clarify disease provide reference direction future research. This offers systematic overview homeostasis roles pathological processes, well effects diseases, particularly cancer.

Language: Английский

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Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(9), P. 1330 - 1351

Published: May 20, 2020

A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single from cancer. We validate the five most abundant flow cytometry silico analyses other cancer types, highlighting their relevance. Myofibroblasts 0 3, characterized extracellular matrix proteins TGFβ signaling, respectively, are indicative primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 CTLA4 protein levels regulatory T lymphocytes (Tregs), which, turn, increases cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific Tregs uncovers role resistance. SIGNIFICANCE: Our work provides significant advance characterizing understanding FAP+ CAF reached high resolution at single-cell level, which enabled us associated with Identification cluster-specific signatures paves way for therapeutic options combination immunotherapies.This article is highlighted In This Issue feature, p. 1241.

Language: Английский

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Physical traits of cancer

Science, Journal Year: 2020, Volume and Issue: 370(6516)

Published: Oct. 29, 2020

The role of the physical microenvironment in tumor development, progression, metastasis, and treatment is gaining appreciation. emerging multidisciplinary field sciences cancer now embraced by engineers, physicists, cell biologists, developmental oncologists attempting to understand how parameters processes affect progression treatment. Discoveries this are starting be translated into new therapeutic strategies for cancer. In Review, we propose four traits tumors that contribute resistance: (i) elevated solid stresses (compression tension), (ii) interstitial fluid pressure, (iii) altered material properties (for example, increased tissue stiffness, which historically has been used detect palpation), (iv) microarchitecture. After defining these traits, discuss their causes, consequences, they complement biological hallmarks

Language: Английский

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Intratumoral heterogeneity in cancer progression and response to immunotherapy

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(2), P. 212 - 224

Published: Feb. 1, 2021

Language: Английский

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Turning cold tumors into hot tumors by improving T-cell infiltration

Theranostics, Journal Year: 2021, Volume and Issue: 11(11), P. 5365 - 5386

Published: Jan. 1, 2021

Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has greatly improved the clinical efficacy of malignant tumor therapy. ICI-mediated antitumor responses depend on infiltration T cells capable recognizing and killing cells. ICIs are not effective in "cold tumors", which characterized lack T-cell infiltration. To realize full potential immunotherapy solve this obstacle, it is essential to understand drivers into tumors. We present a critical review our understanding mechanisms underlying including impaired priming deficient homing beds. "Hot tumors" with significant associated better ICI efficacy. In review, we summarize multiple strategies that promote transformation "hot discuss these lead increased Finally, application nanomaterials provide an outlook future emerging field. The combination nanomedicines enhances cross-presentation antigens promotes A deeper opens new possibilities for development cell-based therapies improve effectiveness.

Language: Английский

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Dynamic EMT: a multi‐tool for tumor progression

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(18)

Published: Aug. 30, 2021

Review30 August 2021Open Access Dynamic EMT: a multi-tool for tumor progression Simone Brabletz Corresponding Author [email protected] orcid.org/0000-0003-0936-1526 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center Molecular Medicine, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany Search more papers by this author Harald Schuhwerk orcid.org/0000-0001-6971-3760 Thomas orcid.org/0000-0003-2983-9048 Marc P. Stemmler orcid.org/0000-0002-7866-3686 Information *,1, Schuhwerk1, Brabletz1 and *,1 1Department *Corresponding author. Tel: +49 9131 85 29101; E-mail: The EMBO Journal (2021)40:e108647https://doi.org/10.15252/embj.2021108647 This article is part the Cancer Reviews 2021 series. PDFDownload PDF text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract process epithelial–mesenchymal transition (EMT) fundamental embryonic morphogenesis. Cells undergoing it lose epithelial characteristics integrity, acquire mesenchymal features, become motile. In cancer, program hijacked confer essential changes in morphology motility that fuel invasion. addition, EMT increasingly understood orchestrate large variety complementary cancer such as cell stemness, tumorigenicity, resistance therapy adaptation microenvironment. review, we summarize recent findings related these various classical non-classical functions, introduce true tumorigenic multi-tool, involved many aspects cancer. We suggest therapeutic targeting will—if acknowledging complexities—be possibility concurrently interfere with on levels. Introduction Epithelial-to-mesenchymal describes transdifferentiation stationary cells mesenchymal, motile phenotype was initially observed early development (Hay, 1995). Here, contributes embryonal processes like gastrulation, neural crest formation, or heart (Thiery et al, 2009; Nieto 2016). also crucial physiological wound healing (Arnoux 2008) tissue homeostasis (Ahmed 2006). Importantly, pathological reactivation plays role diseases organ fibrosis metastasis (Fig 1A), which focus review. Figure 1. Classical functions (A) frequently occurs at invasive front tumors, destroys well-defined structures, allows migrate, invade tissue, intravasate blood lymphatic vessels. Tumor their way through body can travel single cells, clusters exhibiting partial headed leader cell. At secondary site, extravasate colonize distant organ, where MET outgrowth macrometastases. (B) induced mainly set transcription factors (EMT-TFs) ZEB1, ZEB2, SNAIL, SLUG TWIST differ protein structure, size, individual functions. All them are repressors E-cadherin activate markers Vimentin, Fibronectin N-cadherin. Epithelial displaying apical–basal polarity held together tight junctions, adherens desmosomes anchored underlying basement membrane hemidesmosomes. They express three different complexes junctional molecules maintain polarity. EMT, expression EMT-TFs leads inhibition major components structures concomitantly activates genes associated state. gain front–rear polarity, display actin stress fibers, capacities. Notably, very rarely switch completely phenotype, but fluently convert between intermediate states certain features keeping sets characteristics. Further, reversible process. Mesenchymal revert state MET. An important execution played microRNAs miR-200 mir-34 families regulated double-negative feedback loops ZEB1/2 respectively, serve reinforce either Download figure PowerPoint an extremely complex diverse disease not only varying entities, within same entity, subtypes, even subtypes. tumors spatial temporal heterogeneity be elicited, e.g., via occurrence consecutive mutations clonal evolution (McGranahan Swanton, 2017). However, plasticity, allowing continuous adaption ever-changing conditions, mediated genetically fixed, depending accumulating mutations, epigenetically orchestrated signals from microenvironment, rendering whole (by activating mesenchymal–epithelial transition; MET) highly dynamic (see overview Fig 2). 2. Overview summarizing multiple oncogenic course progression. allow invade, intra- sites, enables traits support initiation well metastatic colonization. Throughout progression, they help cope changing conditions metabolic reprogramming, enhanced survival altered DNA repair prevention death, immune evasion improved chemo- radiotherapy. supporting handle environmental extracellular from, CAFs microenvironment approaches. executed core EMT-activating including SNAIL (also SNAI1) SNAI2), basic helix–loop–helix TWIST1 (TWIST) TWIST2 zinc finger E-Box binding homeobox ZEB1 ZEB2. share ability repress encoding gene CDH1 motifs cognate promoter regions (Nieto 2016) shown (Batlle 2000; Cano 2000), (Yang 2004), (Eger 2005), ZEB2 (Comijn 2001). parallel, directly indirectly VIM (Vimentin), FN1 (Fibronectin), CDH2 (N-cadherin) 2016; Dongre Weinberg, 2019) 1B). shared, distinct EMT-TFs, patterns size structure (Stemmler 2019). Beyond "classical" traits, motility, capacities, widespread importance biology indicated additional pleiotropic (Brabletz 2018). have been stemness properties increase linking concept stem (CSCs). Additionally, repair, escape senescence apoptosis, resistance, resulting pro-survival providing advantage under types conditions. Altogether, non-redundant context-dependent dynamically (TME) permanently adapt (Puisieux 2014). Consequently, intervention EMT/plasticity will provide opportunity fight blow. all highlight clinical implications. Classical/core Migration invasion normal form protective sheets structural integrity. connection junction junction, desmosomes, junctions seal located apical constitute barrier solutes water. apical-basal function, has defined "asymmetry" tissues. Polarity complexes, Par, Crumbs, Scribble ensure proper organization versus basolateral domains (Huang 2012). Of note, some control regulate spindle orientation division mode (Martin-Belmonte Perez-Moreno, 2011) Elicited TME, activation toward malignancy, accompanied substantial cellular Cell–cell contacts deconstructed repression CDH1, cadherin (E-cadherin), constituent coding other molecules. As consequence disintegration direct transcriptional several members Crumbs lost (Aigner 2007; Moreno-Bueno 2008; Spaderna Lamouille 2014) coincides profound cytoskeletal reorganization constriction, formation conversion cuboidal columnar shapes spindle-like elongated forms (Moreno-Bueno 2008). Newly formed actin-rich protrusions lamellipodia filopodia movement. To surrounding tissues, induce invadopodia, specialized proteolytic function (Yilmaz Christofori, Eckert 2011; Ridley, Sundararajan 2015). supported induction matrix metalloproteases degradation adjacent tissues (Miyoshi 2004; Miyoshi 2005; Huang 2009) inducers prevent synthesis repressing its (Spaderna events cause loss integrity dissemination thus execute first step cascade 1A). MET: colonization 1990, Fearon Vogelstein proposed meanwhile genetic model colorectal tumorigenesis. described deterioration greater malignancy driven stepwise accumulation hypothesized perpetuates during last established malignant carcinoma metastases, implying metastases most degenerated (Fearon Vogelstein, 1990). efforts identify specific metastasis-associated remained unsuccessful. Rather, already twenty years ago, compared de-differentiated nature primary tumor, exhibit re-differentiated morphology, similar center These led hypothesis de-differentiation transient condition opposing re-differentiation needs initiated advantageous macrometastases (Figs 1A But why do re-differentiate? Invasive, were growth arrested, whereas proliferation detected metastasis, suggesting must reversed order fact inhibit 3). There publications confirming relevance (Chaffer 2006; Korpal Ocana 2012; Tsai perfect accordance failure EMT-causing attributed epigenetic regulation 3. Cellular plasticity governed provided window phenotypes cells. Drug sensitivity, proliferation, response apoptosis highest states, drug efflux, invasion, states. A hybrid provides maximal capacity, changes. Note extreme initiation, lost. Whereas investigated great detail below), less known about trigger reverse Is just lack EMT-inducing stimuli coupled reduced EMT-TFs? Several studies could show knockdown EMT-TF sufficient elicit vitro lines entities depletion Zeb1 mouse pancreatic fixes (Krebs Once ZEB-family (ZEB1 ZEB2) declines, reduction reinforced loop family microRNAs. During ZEB transcriptionally members. Vice versa, post-transcriptional level Thus, bidirectional transitions potentiated ZEB/miR-200 circuit (Bracken Burk Wellner 2009). branch inducible tumor-suppressor p53, miR-200s (Kim 2011). Upregulation consequences. It exerts both invasion- migration-inhibiting, tumor-suppressing (Peter, 2009), promotes (Korpal controversial, EMT-MET adapting respective Similar negative loop, miR-34 regulatory (Siemens Diaz-Lopez target themselves, BMI1, CD44, CD133, JAG1, MYC tumor-relevant "non-classical" discussed below Brabletz, 2010; Since slow multistep take requires different, sometimes apparently spatiotemporal manner, valid investigation remains challenging rely models. Recently, focusing EMT/MET using elegant 2012, al (2012) demonstrated induction, case TWIST, supports skin subsequent Twist1 downregulation necessary (Tsai 2012) Another study necessity MMTV-PyMT breast disseminate lung. EMT-state niche local fibroblasts turn (MET) (del Pozo Martin Esposito colleagues found E-selectin adhesion bone vascular elicits (Esposito summary, reports significance detailed still need further investigation. Partial long viewed binary separate populations. past, narrow perspective challenged means metastasis. One example analysis Fischer Fsp1-Cre lineage tracing Based finding lung consist had never switched full Fsp1+ authors concluded (Fischer nowadays accepted that, although reactivated types, fully end-stage Vimentin often expressed. rather gradual incomplete, termed Pastushenko Blanpain, 2019; Yang 2020) Over years, report vivo detection carrying combination markers. Already 1990s, analyses reported observations (Mareel 1992; Birchmeier Behrens, 1994). Later, circulating (CTCs) simultaneous (Yu 2013). Similarly, identified co-expression (EpCAM+) (Vim+) marker autochthonous murine prostate (Ruscetti linked single-cell transcriptomics head neck (Puram group occurring introduced term "hybrid" (Pastushenko 2018; 2021) Moreover, Bornes used (2015) incapable detecting majority disseminating partial/hybrid 2015; does mean important. evidence traps profoundly suppresses mammary (Ye oncogene-induced model, Xu (2017) required small subset (Xu Interestingly, modes involve levels observed. groups forming clusters. Indeed, type "collective migration" might common than dissemination, approaches clustered circulation (Friedl Aceto 2014; Cheung Nevertheless, despite appearance, characteristic detectable migrating (Aiello 2018), follow "leader" pave "follower" (Matise Chen Non-classical Besides drive phenotypes, regulating tumorigenesis Regulation Normal dependent source replenish dying committed terminally differentiated tissue. observation maintained after transplantations into mice, prompted (Reya Simplified, measured capability fractions mice. Strikingly, capacity increasing Shibue 2017; Wilson Overexpression SNAI1, TWIST1, CD44+/CD24lo pool, increased sphere vitro, elevated tumorigenicity (Mani Morel determines healthy gland converts luminal settings (Guo results obtained key determinant reciprocal ZEB1/miR-200 controlling BMI1 SOX2 (Shimono Krebs squamous (SCC) cooperatively CDKN2A (p16INK4A) promote capacities 2010). protocadherin FAT1 one player stemness. inactivated SCC involving CAMK2, SRC activities nuclear translocation YAP1 2021). another promoting factor, PRRX1, thereby uncoupling EMT/migration (Ocana PRRX1 isoform switching driving force (Takano Mechanistically, realm correlate gradually efficiencies seeding line idea addition (Shibue 2013; 2020), transformation. upregulation RAS transformed bronchial unleash favoring aggressive undifferentiated (Morel Liu 2014b; Larsen KRAS dependency (KRAS addiction) thresholds KRAS-dependent (Singh 2014b). effects evident ectopic Zeb2 intestinal epithelium transgenic Elevation generates absence cooperating defects (Slowicka 2020). Therapy Loss durable efficacy relapse initial successful treatment obstacles battle against Conventional favorably eliminating non-stem cell-like fails deplete properties. Settleman, Santamaria Dudas signatures acquisition strongly correlated, standard targeted EGFR PI3K inhibitors (Creighton Farmer Byers For example, gemcitabine-resistant Panc1 sensitized upon (Wellner routes include efflux evading anoikis former ATP-binding cassette (ABC) transporter family, FOXC1 (Aller Singh Saxena contribute therapy-induced interfering p53 PTEN, BCL-XL (Vega Escriva Kurrey Wu Cao Experimentally HMLER 10-fold IC50 doses chemotherapeutics (Gupta Tulchinsky experiments, GFP-labeled PyMT high cyclophosphamide non-small-cell (NSCLC), AXL receptor tyrosine kinase inhibition, sustained activity Sequist Zhang Furthermore, HDAC class I demethylation resensitizes osteosarcoma chemotherapy (Meidhof

Language: Английский

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Cholangiocarcinoma

Nature Reviews Disease Primers, Journal Year: 2021, Volume and Issue: 7(1)

Published: Sept. 9, 2021

Cholangiocarcinoma (CCA) is a highly lethal adenocarcinoma of the hepatobiliary system, which can be classified as intrahepatic, perihilar and distal. Each anatomic subtype has distinct genetic aberrations, clinical presentations therapeutic approaches. In endemic regions, liver fluke infection associated with CCA, owing to oncogenic effect chronic biliary tract inflammation. other CCA inflammation choledocholithiasis, cholelithiasis, or primary sclerosing cholangitis, but most CCAs have no identifiable cause. Administration anthelmintic drug praziquantel decreases risk from flukes, reinfection common future vaccination strategies may more effective. Some patients are eligible for potentially curative surgical options, such resection transplantation. Genetic studies provided new insights into pathogenesis two aberrations that drive non-fluke-associated intrahepatic fibroblast growth factor receptor 2 fusions isocitrate dehydrogenase gain-of-function mutations, therapeutically targeted. desmoplastic cancer targeting tumour immune microenvironment might promising approach. remains disease further scientific needed improve patient outcomes. system often This Primer reviews epidemiology, pathophysiological mechanisms, diagnosis management cholangiocarcinoma, highlights experience directions.

Language: Английский

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The inflammatory pathogenesis of colorectal cancer

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(10), P. 653 - 667

Published: April 28, 2021

Language: Английский

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