Browsing by Subject "Lung Cancer"

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    IL-9 Intrinsically Alters Gene Expression and Chromatin Structure in Pulmonary Macrophages to Enhance Lung Tumor Growth
    (2025-04) Cannon, Anthony Michael; Kaplan, Mark H.; Jerde, Travis; Brutkiewicz, Randy; Snell, Laura
    Tumor-associated macrophages are an abundant, tumor-infiltrating cell population that support tumor progression through mechanisms such as extracellular matrix remodeling, immunosuppression, and metabolic reprogramming. The cytokine milieu is a factor that influences the functional phenotype of TAMs within the tumor microenvironment. Among these, interleukin-9 (IL-9) is a pleiotropic cytokine with both tumor-promoting and tumor-suppressing roles depending on the cancer type and responding cell. Importantly, mechanistic understanding of IL-9 in cancer is largely undefined. The work described in this thesis mechanistically defines the role of IL-9-responsive macrophages in the progression and metastasis of lung tumors. We demonstrate that IL-9 expands lung interstitial macrophage populations and induces the expression of Arginase 1 (ARG1), a critical enzyme in arginine to polyamine metabolism that is associated with poor survival in patients. Therapeutically, targeting ARG1-expressing macrophages using Arg1 siRNA-loaded nanoparticles significantly reduced polyamine levels and tumor burden. Additionally, bulk RNA sequencing and single-nuclei multi-modal ATAC and RNA sequencing in mixed-bone marrow chimeric mice revealed that IL-9 intrinsically reprograms the epigenetic and transcriptomic landscape of lung interstitial macrophages. Dysregulation of key genes, including Pdl1 and several cathepsins (Ctsd, Ctse, and Ctss), was identified and linked to increased tumor growth and an impaired anti-tumor immune response. In summary, this work identifies a critical vii pro-tumor mechanism of IL-9 in lung interstitial macrophages, characterized by dysregulated arginine metabolism, altered macrophage gene expression, and reduced anti-tumor immune responses. These findings underscore the potential of targeting IL-9-mediated pathways in macrophages as a potential therapeutic approach in lung cancer and metastasis.
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    Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
    (Springer Nature, 2019-01-07) Erzurumluoglu, A. Mesut; Liu, Mengzhen; Jackson, Victoria E.; Barnes, Daniel R.; Datta, Gargi; Melbourne, Carl A.; Young, Robin; Batini, Chiara; Surendran, Praveen; Jiang, Tao; Adnan, Sheikh Daud; Afaq, Saima; Agrawal, Arpana; Altmaier, Elisabeth; Antoniou, Antonis C.; Asselbergs, Folkert W.; Baumbach, Clemens; Bierut, Laura; Bertelsen, Sarah; Boehnke, Michael; Bots, Michiel L.; Brazel, David M.; Chambers, John C.; Chang-Claude, Jenny; Chen, Chu; Corley, Janie; Chou, Yi-Ling; David, Sean P.; Boer, Rudolf A. de; Leeuw, Christiaan A. de; Dennis, Joe G.; Dominiczak, Anna F.; Dunning, Alison M.; Easton, Douglas F.; Eaton, Charles; Elliott, Paul; Evangelou, Evangelos; Faul, Jessica D.; Foroud, Tatiana; Goate, Alison; Gong, Jian; Grabe, Hans J.; Haessler, Jeff; Haiman, Christopher; Hallmans, Göran; Hammerschlag, Anke R.; Harris, Sarah E.; Hattersley, Andrew; Heath, Andrew; Hsu, Chris; Iacono, William G.; Kanoni, Stavroula; Kapoor, Manav; Kaprio, Jaakko; Kardia, Sharon L.; Karpe, Fredrik; Kontto, Jukka; Kooner, Jaspal S.; Kooperberg, Charles; Kuulasmaa, Kari; Laakso, Markku; Lai, Dongbing; Langenberg, Claudia; Le, Nhung; Lettre, Guillaume; Loukola, Anu; Luan, Jian’an; Madden, Pamela A. F.; Mangino, Massimo; Marioni, Riccardo E.; Marouli, Eirini; Marten, Jonathan; Martin, Nicholas G.; McGue, Matt; Michailidou, Kyriaki; Mihailov, Evelin; Moayyeri, Alireza; Moitry, Marie; Müller-Nurasyid, Martina; Naheed, Aliya; Nauck, Matthias; Neville, Matthew J.; Nielsen, Sune Fallgaard; North, Kari; Perola, Markus; Pharoah, Paul D. P.; Pistis, Giorgio; Polderman, Tinca J.; Posthuma, Danielle; Poulter, Neil; Qaiser, Beenish; Rasheed, Asif; Reiner, Alex; Renström, Frida; Rice, John; Rohde, Rebecca; Rolandsson, Olov; Samani, Nilesh J.; Samuel, Maria; Schlessinger, David; Scholte, Steven H.; Scott, Robert A.; Sever, Peter; Shao, Yaming; Shrine, Nick; Smith, Jennifer A.; Starr, John M.; Stirrups, Kathleen; Stram, Danielle; Stringham, Heather M.; Tachmazidou, Ioanna; Tardif, Jean-Claude; Thompson, Deborah J.; Tindle, Hilary A.; Tragante, Vinicius; Trompet, Stella; Turcot, Valerie; Tyrrell, Jessica; Vaartjes, Ilonca; Leij, Andries R. van der; Meer, Peter van der; Varga, Tibor V.; Verweij, Niek; Völzke, Henry; Wareham, Nicholas J.; Warren, Helen R.; Weir, David R.; Weiss, Stefan; Wetherill, Leah; Yaghootkar, Hanieh; Yavas, Ersin; Jiang, Yu; Chen, Fang; Zhan, Xiaowei; Zhang, Weihua; Zhao, Wei; Zhao, Wei; Zhou, Kaixin; Amouyel, Philippe; Blankenberg, Stefan; Caulfield, Mark J.; Chowdhury, Rajiv; Cucca, Francesco; Deary, Ian J.; Deloukas, Panos; Angelantonio, Emanuele Di; Ferrario, Marco; Ferrières, Jean; Franks, Paul W.; Frayling, Tim M.; Frossard, Philippe; Hall, Ian P.; Hayward, Caroline; Jansson, Jan-Håkan; Jukema, J. Wouter; Kee, Frank; Männistö, Satu; Metspalu, Andres; Munroe, Patricia B.; Nordestgaard, Børge Grønne; Palmer, Colin N. A.; Salomaa, Veikko; Sattar, Naveed; Spector, Timothy; Strachan, David Peter; Harst, Pim van der; Zeggini, Eleftheria; Saleheen, Danish; Butterworth, Adam S.; Wain, Louise V.; Abecasis, Goncalo R.; Danesh, John; Tobin, Martin D.; Vrieze, Scott; Liu, Dajiang J.; Howson, Joanna M. M.; Medical and Molecular Genetics, School of Medicine
    Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.