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Using a colitis-associated cancer model and LRRK2 G2019S knock-in mice, the study shows increased tumor number and size, enhanced intestinal epithelial proliferation, and intensified inflammation in the tumor microenvironment. Mechanistically, G2019S mice show greater susceptibility to DSS-induced colitis, and LRRK2 kinase inhibition reduces severity and colorectal tumor progression by attenuating inflammasome activation, gut epithelium necrosis, and improving GSDMD inhibitor responses.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lrrk2-g2019s-promotes-colon-cancer-potentially-via-lrrk2-gsdmd-axis-mediated-gut-inflammation/339177/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lrrk2-g2019s-promotes-colon-cancer-potentially-via-lrrk2-gsdmd-axis-mediated-gut-inflammation/339177.png","ImageObject",300,407,{"name":92,"@type":93},"Ava Thompson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",15,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the study’s main finding about LRRK2 G2019S in colon cancer?","Question",{"text":113,"@type":114},"LRRK2 G2019S promotes colitis-associated colon cancer, increasing tumor number and size while strengthening epithelial proliferation and inflammation in the tumor microenvironment.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does LRRK2 G2019S influence DSS-induced colitis and cancer progression?",{"text":118,"@type":114},"KI mice show heightened susceptibility to DSS-induced colitis, and blocking LRRK2 kinase activity ameliorates colitis severity and CAC progression.",{"name":120,"@type":111,"acceptedAnswer":121},"What role do inflammasome activation and GSDMD inhibitors play?",{"text":122,"@type":114},"LRRK2 G2019S drives inflammasome activation and exacerbates gut epithelial necrosis; GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},339177,1790097023,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},1649267921044,"https://us-avatar.wpscdn.com/avatar/1800007509477c92dfb?_k=1786009248482753345","cells  \nArticle  \nLRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation  \nYuhang Wang 1, Joyce Z. Gao 1, Taylor Sakaguchi 1, Thorsten Maretzky 2, Prajwal Gurung 2, Nandakumar S. Narayanan 3,4, Sarah Short 2, Yiqin Xiong 1 and Zizhen Kang 1, *  \nCitation: Wang, Y.; Gao, J.Z.; Sakaguchi, T.; Maretzky, T.; Gurung, P.; Narayanan, N.S.; Short, S.; Xiong, Y.; Kang, Z. LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2–GSDMD Axis-Mediated Gut Inflammation. Cells 2024, 13, 565 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells13070565  \nAcademic Editor: Alexander E. Kalyuzhny  \nReceived: 20 February 2024  \nRevised: 20 March 2024  \nAccepted: 22 March 2024  \nPublished: 23 March 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Pathology, University of Iowa, Iowa City, IA 52242, USA  \n2 Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA  \n3 Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA  \n4 Department of Neurology, University of Iowa, Iowa City, IA 52242, USA  \n* Correspondence: [zizhen-kang@uiowa.edu](zizhen-kang@uiowa.edu)  \nAbstract: Leucine-rich repeat kinase 2 (LRRK2) is a serine–threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson’s disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.  \nKeywords: LRRK2 G2019S; colitis; colon cancer; inflammation  \n1. Introduction  \nLeucine-rich repeat kinase 2 (LRRK2) stands as a pivotal serine–threonine protein kinase within the expansive ROCO protein family, characterized by its multifaceted structure encompassing distinct domains. Among these domains are the N-terminal armadillo domain, ankyrin repeats, leucine-rich repeat (LRR) domain, Ras of complex protein domain (Roc) GTPase, C-terminal of Roc (COR) domain, kinase domain and a C-terminal WD40 domain [1,2] . The breadth of LRRK2 functions extends across diverse cellular processes, including autophagy, lysosome function, endocytosis and modulation of the Golgi network [3–5] . Recent insights have underscored LRRK2’s crucial involvement in immune regulation [6,7] . We previously identified LRRK2 as a novel modulator of the activation of the NLRC4 inflammasome [8] . Of note, LRRK2 was first identified in 2004 as a genetic cause of Parkinson’s disease (PD) ","cbCainSW28sQwMUo","https://ap.wps.com/l/cbCainSW28sQwMUo","pdf",6302711,22,"English","# Introduction\n## LRRK2 biology and G2019S links to disease\n## Inflammation and colitis-associated colorectal cancer models","[{\"question\":\"What is the study’s main finding about LRRK2 G2019S in colon cancer?\",\"answer\":\"LRRK2 G2019S promotes colitis-associated colon cancer, increasing tumor number and size while strengthening epithelial proliferation and inflammation in the tumor microenvironment.\"},{\"question\":\"How does LRRK2 G2019S influence DSS-induced colitis and cancer progression?\",\"answer\":\"KI mice show heightened susceptibility to DSS-induced colitis, and blocking LRRK2 kinase activity ameliorates colitis severity and CAC progression.\"},{\"question\":\"What role do inflammasome activation and GSDMD inhibitors play?\",\"answer\":\"LRRK2 G2019S drives inflammasome activation and exacerbates gut epithelial necrosis; GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice.\"}]","LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation | PDF",1790028396,55]