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Findings indicate LIF reduces invasive and EMT-linked programs in GC cell lines and patient-derived xenografts by activating Hippo signaling and repressing YAP/TAZ activity, lowering CD44v3 expression and metastatic potential in vivo.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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problem does the study address in gastric cancer treatment?","Question",{"text":63,"@type":64},"Gastric cancer is often diagnosed at metastatic stages with high relapse rates and poor survival, creating a need for better-targeted anti-metastatic therapies.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What is the role of metastasis-initiating cancer stem cells (MIC) in this research?",{"text":68,"@type":64},"MICs are a rare cancer stem cell population with self-renewal and chemo-/radio-resistant properties that can initiate metastases and drive recurrence.",{"name":70,"@type":61,"acceptedAnswer":71},"How does leukaemia inhibitory factor (LIF) affect gastric cancer cells and signaling?",{"text":72,"@type":64},"LIF decreases invasion and EMT-associated programs by activating Hippo kinases and repressing YAP/TAZ oncogenic signaling, including reduced CD44v3 expression and lower metastatic potential in 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metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor  \nLornella Seeneevassen 1, Anissa Zaafour1, Elodie Sifré 1, Coralie Genevois1,2, Tra Ly Nguyen1, Yasmine Pobiedonoscew 1, Alban Giese1, Jérôme Guignard 1, Camille Tiffon1, Benoit Rousseau3, Anne-Aurélie Raymond4, Geneviève Belleannée5,6, Hélène Boeuf7,  \nCaroline Gronnier 1,5,8, Océane C. B. Martin1, Julie Giraud 1, Philippe Lehours 1,5,9, Pierre Dubus1,5,6 and Christine Varon 1 ✉  \n© The Author(s) 2024  \nINTRODUCTION  \nGC is a deadly disease accounting for ~768,793 deaths worldwide in 2020, making it the 4th leading cause of cancer-related death [1] . GC therapy comprises surgery with additional adjuvant or neoadjuvant chemo-and radio-therapies and the number of relapses remains high. Surgical resection which remains the only curative therapeutic option is possible in case of early tumours but GC is commonly a late-diagnosed disease with 80% of patients detected at metastatic state and with a 5-year survival rate of \u003C5%[2, 3] . It is thus crucial to find appropriate diagnostic tools for earlier detection of GC as well as strategies for better-targeted therapy of disseminated cancers.  \nThe most aggressive component of heterogeneous gastric tumours is the rare population of cancer stem cells (CSC) which carry specific self-renewal and chemo-/radio-resistant properties [4–7], allowing them to initiate tumours and cause recurrence. In the metastatic process, part of these CSC corresponding to metastasis-initiating CSC (MIC), is able to acquire invasive characteristics, evade the primary tumour, disseminate, and colonise distant organs to initiate metastases [8, 9] . We have recently identified CD44v3+ cells as MIC in gastric tumours, associated with bad prognosis in GC [8] and which could constitute an interesting therapeutical target for GC metastatic  \ndisease. CD44v3+ cells are a subpopulation of gastric CD44+ CSC and our previous work has demonstrated an enrichment of the Hippo pathway oncogenic members Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in GC and especially in gastric CSC [10–12] . YAP and TAZ are welldescribed for their role in invasion and metastasis and their targeting could affect GC MIC.  \nWe have demonstrated that activating the Hippo kinase core with leukaemia inhibitory factor (LIF) decreases tumorigenic properties of gastric CSC [4] . Nevertheless, LIF/LIF receptor (LIFR) signalling was never tested in the gastric metastatic context despite its promising anti-metastatic effects in hepatocellular carcinoma [13], clear cell renal carcinoma [14] and breast cancer [15].  \nLIF–LIF receptor (LIFR) canonical pathway is mediated by JAK/ STAT activation, causing STAT3 phosphorylation, dimerisation, and nuclear translocation, resulting in the transcription of target genes involved in cell survival and tumorigenesis [16] . Other cell signalisation processes have been identified downstream of LIFLIFR, which could explain its pleiotropy [16–23] . Nonetheless, LIFLIFR-dependent anti-metastatic properties in breast cancer implicated the Hippo pathway activation [15] .  \nThe aim of this study was to decipher LIF’s potential as antimetastatic therapy in GC and the underlying signalling  \n1INSERM U1312, Bordeaux Institute of Oncology, University of Bordeaux, 33076 Bordeaux, France. 2VIVOPTIC TBM-Core, University Bordeaux, CNRS UAR3427 INSERM US005, 33076 Bordeaux, France. 3Animal Facility, University of Bordeaux, 33076 Bordeaux, France. 4Oncoprot TBM-Core, University of Bordeaux, CNRS UAR3427 INSERM US005, 33076 Bordeaux, France. 5CHU Bordeaux, F-33076 Bordeaux, France. 6Department of Histology and Pathology, CHU Bordeaux, F-33000 Bordeaux, France. 7INSERM U1026, Tissue Bioengineering, University of Bordeaux, Bordeaux, France. 8Department of Digestive Surgery, Haut-Lévêque Hospital, F-33000 Bordeaux, France. ","cbCaiaPYnSkjT6sd","https://ap.wps.com/l/cbCaiaPYnSkjT6sd","pdf",10539633,13,"English","# Introduction\n## Cancer stem cells and metastasis in gastric cancer\n## LIF signaling and rationale for anti-metastatic therapy\n# Results\n## LIF reduces EMT- and invasion-related gene expression in GC cells","[{\"question\":\"What problem does the study address in gastric cancer treatment?\",\"answer\":\"Gastric cancer is often diagnosed at metastatic stages with high relapse rates and poor survival, creating a need for better-targeted anti-metastatic therapies.\"},{\"question\":\"What is the role of metastasis-initiating cancer stem cells (MIC) in this research?\",\"answer\":\"MICs are a rare cancer stem cell population with self-renewal and chemo-/radio-resistant properties that can initiate metastases and drive recurrence.\"},{\"question\":\"How does leukaemia inhibitory factor (LIF) affect gastric cancer cells and signaling?\",\"answer\":\"LIF decreases invasion and EMT-associated programs by activating Hippo kinases and repressing YAP/TAZ oncogenic signaling, including reduced CD44v3 expression and lower metastatic potential in vivo.\"}]","Targeting metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor | PDF",1789976420,33]