Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention

O’Connor, Tracy; Zhou, Xiaolan; Kosla, Jan; Adili, Arlind; Beccaria, Maria Garcia; Kotsiliti, Eleni; Pfister, Dominik; Johlke, Anna Lena; Sinha, Ankit; Sankowski, Roman; Schick, Markus; Lewis, Richard T.; Dokalis, Nikolaos; Seubert, Bastian; Höchst, Bastian; Inverso, Donato; Heide, Danijela; Zhang, Wenlong; Weihrich, Petra; Manske, Katrin; Wohlleber, Dirk; Anton, Martina; Hoellein, Alexander; Seleznik, Gitta Maria; Bremer, Juliane; Bleul, Sabine; Augustin, Hellmut G.; Scherer, Florian; Koedel, Uwe; Weber, Achim; Protzer, Ulrike; Förster, Reinhold; Wirth, Thomas; Aguzzi, Adriano; Meissner, Felix; Prinz, Marco; Baumann, Bernd; Höpken, Uta E.; Knolle, Percy A.; Baumgarten, Louisa von; Keller, Ulrich; Heikenwälder, Mathias

doi:10.1016/j.ccell.2019.08.001

Cited by 27 publications

(30 citation statements)

References 78 publications

(71 reference statements)

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“…f Circular workflow of functional interrogations in mouse models of cancer harboring defined genetic lesions, investigation of genetically unmanipulated mouse tumors in a clinical trial-like setting in vivo, and cross-species application of the genetic determinants of novel biological functions and intervention-evoked dynamic state switches learned therein in corresponding human cancer patient cohorts. exploration of functional lymphoma features in Eµ-myc mice and the subsequent validation of these findings in human DLBCL 23,27,28,40,[54][55][56] , we certainly acknowledge limitations of this transgenic model as a reflection of DLBCL pathogenesis, particularly in light of numerous mouse models developed to more faithfully recapitulate GCB-or ABC-subtype features of human DLBCL [57][58][59][60][61][62][63][64][65][66][67][68] . However, while those models elegantly provide examples for distinct routes into GCB-or ABC-skewed diffuse large B-cell lymphomagenesis, they are, in turn, selectively composed of complexity-reduced genetics out of the overwhelming heterogeneity human DLBCL exhibit as a cardinal property.…”

Section: Discussionmentioning

confidence: 99%

H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients

et al. 2020

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Lesion-based targeting strategies underlie cancer precision medicine. However, biological principlessuch as cellular senescenceremain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and crossspecies validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomaswith and without defined genetic lesionsrecapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss-and gain-offunction genetics, and an unbiased clinical trial-like approach. A mouse-derived senescenceindicating gene signature, termed "SUVARness", as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic.

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Section: Discussionmentioning

confidence: 99%

H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients

et al. 2020

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“…26 Previous studies have proposed that CCL19 could regulate inflammation in central nervous system lymphoma and allergic lung inflammation. 27,28 Additionally, CCL19 is implicated in the process of fibrosis in the lung and liver. 29,30 Consistent with previous study, in our exploration, CCL19 presented relatively high expression in HG-induced HK-2 and HMC cells, and suppressed cell viability as well as promoted cell inflammation and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

MiR‐325‐3p inhibits renal inflammation and fibrosis by targeting CCL19 in diabetic nephropathy

Sun

Wang

et al. 2020

Clin Exp Pharma Physio

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Diabetic nephropathy (DN) is the primary cause of end-stage renal disease, 1 and causes cardiovascular mortalities for patients with obesity or diabetes. 2 The typical structural characteristics of DN are thickening of tubular basement membranes and glomerular hypertrophy resulting from the aberrant deposition of the extracellular matrix (ECM) in the kidneys. 3 Additionally, renal dysfunction caused by DN is closely related to ECM deposition in glomerular mesangium and tubulointerstitium. 4 Tubulointerstitial fibrosis and glomerulosclerosis are the key factors of DN. 5,6 Unfortunately, effective therapeutic methods for DN have not been discovered, thus, further exploration of the molecular mechanisms in the pathophysiology of DN is in urgent need. MicroRNAs (miRNAs) are a category of non-coding RNA (ncRNA) molecules with 20-24 nucleotides in length. 7 Dysregulation of miR-NAs has been reported to regulate several biological process during the progression of DN. 8,9 In detail, miRNA-23a/27a attenuates renal fibrosis through muscle-kidney crosstalk in streptozotocin-induced diabetic mice. 10 Furthermore, miR-21 promotes renal tubular extracellular matrix (ECM) synthesis and accumulation to aggravate renal fibrosis in DN. 11 Most recently, miR-325-3p was confirmed to get involved in immobilization-induced suppression of luteinizing hormone translation and secretion. 12 Besides, miR-325-3p suppresses

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“…As a potential immune stimulator, CCL19 has been observed to be increased in lung cancer, and an association between CCL19 expression and high TNM staging and vascular invasion was identified [ 36 ]. CCL19 enhances parenchymal central nervous system (CNS) retention of lymphoma cells (LCs), thereby promoting central nervous system lymphoma (CNSL) formation [ 37 ]. Xu et al identified that CCL19 suppressed angiogenesis in CRC via promoting miR-206 [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients

et al. 2020

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Background The epithelial-mesenchymal transition (EMT) plays a pivotal role in various physiological processes, such as embryonic development, tissue morphogenesis, and wound healing. EMT also plays an important role in cancer invasion, metastasis, and chemoresistance. Additionally, EMT is partially responsible for chemoresistance in colorectal cancer (CRC). The aim of this research is to develop an EMT-based prognostic signature in CRC. Methods RNA-seq and microarray data, together with clinical information, were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. A total of 244 differentially expressed EMT-related genes (ERGs) were obtained by comparing the expression between normal and tumor tissues. An EMT-related signature of 11 genes was identified as crucially related to the overall survival (OS) of patients through univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and Cox regression analysis. Finally, we established a clinical nomogram to predict the survival possibility of CRC patients by integrating clinical characteristics and the EMT-related gene signature. Results Two hundred and forty-four differentially expressed ERGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that EMT-related signaling pathway genes were highly related to CRC. Kaplan-Meier analysis revealed that the 11-EMT signature could significantly distinguish high- and low-risk patients in both TCGA and GEO CRC cohorts. In addition, the calibration curves verified fine concordance between the nomogram prediction model and actual observation. Conclusion We developed a novel EMT-related gene signature for the prognosis prediction of CRC patients, which could improve the individualized outcome prediction in CRC.

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Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention

Cited by 27 publications

References 78 publications

H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients

H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients

MiR‐325‐3p inhibits renal inflammation and fibrosis by targeting CCL19 in diabetic nephropathy

Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients

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