We discuss This adds to the current evidence that SOX11 is a gene involved in palatogenesis.
◥Collagen remodeling contributes to many physiologic and pathologic processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison with normal tissues. Consequently, genetic or pharmacologic restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:
This collaborative essay, structured as a collection of tales akin to Chaucer's, provides a multiperspectival reflection on enhancement study days, entitled 'Chaucer's World', co-organised by the University of Oxford, the Ashmolean Museum, the Bodleian Library, and secondary schools from the area. The event is aimed at UK secondary school students in their final two years of study, and is intended not only to help students with their preparation for the A-Level English Literature exam but also to instil in them appreciation for Chaucer's works, as well as for medieval literature and culture in general.
Introduction Lung cancer is the most common cause of cancer-related death. Carcinogenic and endogenous processes driving somatic mutation acquisition in cancer can be extracted and defined as mutational signatures using whole genome sequencing (WGS). Tobacco smoke is the main aetiological cause of lung cancer, with mutational signature 4 representing the characteristic C>A transversions produced by smoking. Whilst smoking cessation has been shown to reduce lung cancer risk in epidemiological studies, there has been little exploration into the persistence of smoking 4 in NSCLC genomes after a patient has quit smoking. We investigated the extent and persistence of signature 4 in NSCLC genomes of current, ex- and never-smokers, correlating in particular with clinical history of smoking cessation. Methods 132 NSCLC samples were resected from 131 patients in Greater Manchester. These samples were submitted to the 100,000 Genomes Project (Genomics England). WGS was performed on tumour specimens and matched blood samples. Data generated was processed by a standard pipeline devised by Genomics England. Tumour mutational burden (TMB), mutational signatures and copy number variation (CNV) were obtained. Clinical data collected included: smoking status, date of diagnosis, TNM stage, date of relapse and date of death (where relevant). Fisher's exact tests and Kruskal-Wallis tests were used for statistical comparisons, with Kaplan-Meier plots for survival. Results Signature 4 was associated with a smoking history in 102/119 (85.7%) NSCLCs with a detailed smoking history available. In 17/119 (14.3%) patients with a smoking history but no signature 4 NSCLC, 15/17 (88.2%) patients quit smoking a median of 22 years ago (range 0.006 - 45 years). 6/7 (85.7%) never-smoker NSCLCs were non-signature 4 NSCLCs. 60/75 (80%) ex-smokers had sufficient smoking data to assess signature 4 persistence. Signature 4 endured in the lung tissue prior to tumour diagnosis for a median of 180 months (15 years) (range 1 - 600 months). There was no association between the time of smoking cessation and the time to NSCLC diagnosis (R2=0.0009, p=0.82). Non-signature 4 NSCLCs had a more diverse signature profile (signature 4: mean 4.36, 95% CI 4.13-4.58; non-signature 4: mean 5.52, 95% CI 4.95-6.09; p=<0.0001) with a lower TMB (signature 4: median 9.76/Mb, 95% CI 9.8-12.7; non-signature 4: median 2.02/Mb, 95% CI 1.3-9.3; p=<0.0001). There was no difference in relapse-free survival between signature 4 and non-signature 4 patients with early stage disease (signature 4: median 456 days, HR 0.999, 95% CI 0.419-2.385; non-signature 4: median 319 days, HR 1.001, 95% CI 0.417-2.399). Conclusion The genomic alterations introduced by smoking persist for many years after smoking cessation. NSCLCs arising from smoking carry a distinctive identity compared to those from never-smokers, with higher TMBs driven primarily by signature 4. Whilst survival analysis is limited in this cohort, the pervasive contributions from smoking suggest that lung cancer screening programmes should include all patients with a smoking history. Citation Format: Pantelis A. Nicola, Shereen Rafee, George Burghel, Andrew Wallace, Helene Schlecht, Eleanor Baker, Katie Baker, Lynsey Priest, Mathew Carter, Sharzad Moghadam, Jane Rogan, Robert G. Bristow, William Newman, Fiona H. Blackhall, Colin Lindsay. Persistence of smoking signature 4 in the non-small cell lung cancer genome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3810.
JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.
<p>Supplementary Materials and Methods; Supplementary Figures S1 to S8; Supplementary Figure S1. WISP2 inhibits WISP1-induced Col I linearization; Supplementary Figure S2. WISP2 is less abundant in tumors than in adjacent normal tissues and is an inhibitor of WISP1-induced tumor cell invasion though Col I; Supplementary Figure S3. The C-terminal domain of WISP1 drives WISP1-induced cell invasion through Col I but is dispensable for WISP1-Col I binding; Supplementary Figure S4. Wisp1 is expressed by tumor cells and cancer-associated fibroblast (CAF)-enriched stromal cells isolated from primary breast tumors; Supplementary Figure S5. WISP2 and WISP1DCT block TGFb1-induced cell invasion through Col I by acting as WISP1 antagonists; Supplementary Figure S6. WISP2 limits collagen linearization but does not affect total type I collagen levels in 4T1 breast tumors; Supplementary Figure S7. WISP2 limits collagen linearization in aggressive 4T1-Wisp1 tumors and inhibits breast cancer metastasis; Supplementary Figure S8. WISP1 promotes whereas WISP2 inhibits human breast cancer metastasis; Supplementary Tables S1 to S3; Supplementary Table S1. gBlock sequence for the generation of pCDH-EF1-Wisp2+CTT2A- puro from pCDH-EF1-Wisp2-T2A-puro; Supplementary Table S2. Primers used for cloning; Supplementary Table S3. gRNAs targeting Wisp1 and of non-targeting control gRNAs; Supplementary References</p>
<div>Abstract<p>Collagen remodeling contributes to many physiologic and pathologic processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that <i>WISP2</i> expression is lower in most solid tumors, in comparison with normal tissues. Consequently, genetic or pharmacologic restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis <i>in vivo</i> in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:WISP1 ratio.</p>Significance:<p>Two secreted factors, WISP1 and WISP2, antagonistically regulate collagen linearization, and therapeutically increasing the WISP2:WISP1 ratio in tumors limits collagen linearization and inhibits metastasis.</p><p><i>See related commentary by Barcus and Longmore, p. 5611</i></p></div>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.