{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T15:54:48Z","timestamp":1783612488518,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CIHR project","award":["2022\u20132027"],"award-info":[{"award-number":["2022\u20132027"]}]},{"name":"CIHR project","award":["2020\u20132022"],"award-info":[{"award-number":["2020\u20132022"]}]},{"name":"CIHR project","award":["#35376"],"award-info":[{"award-number":["#35376"]}]},{"name":"CIHR project","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"CIHR project","award":["258000"],"award-info":[{"award-number":["258000"]}]},{"name":"CIHR project","award":["258259"],"award-info":[{"award-number":["258259"]}]},{"name":"CIHR-NCOHR","award":["2022\u20132027"],"award-info":[{"award-number":["2022\u20132027"]}]},{"name":"CIHR-NCOHR","award":["2020\u20132022"],"award-info":[{"award-number":["2020\u20132022"]}]},{"name":"CIHR-NCOHR","award":["#35376"],"award-info":[{"award-number":["#35376"]}]},{"name":"CIHR-NCOHR","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"CIHR-NCOHR","award":["258000"],"award-info":[{"award-number":["258000"]}]},{"name":"CIHR-NCOHR","award":["258259"],"award-info":[{"award-number":["258259"]}]},{"name":"CBIE-FMP","award":["2022\u20132027"],"award-info":[{"award-number":["2022\u20132027"]}]},{"name":"CBIE-FMP","award":["2020\u20132022"],"award-info":[{"award-number":["2020\u20132022"]}]},{"name":"CBIE-FMP","award":["#35376"],"award-info":[{"award-number":["#35376"]}]},{"name":"CBIE-FMP","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"CBIE-FMP","award":["258000"],"award-info":[{"award-number":["258000"]}]},{"name":"CBIE-FMP","award":["258259"],"award-info":[{"award-number":["258259"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["2022\u20132027"],"award-info":[{"award-number":["2022\u20132027"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["2020\u20132022"],"award-info":[{"award-number":["2020\u20132022"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["#35376"],"award-info":[{"award-number":["#35376"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["258000"],"award-info":[{"award-number":["258000"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["258259"],"award-info":[{"award-number":["258259"]}]},{"name":"CAPES-Print Fellowships (LRCC and SBSCC), Federal University of Para\u00edba, Brazil","award":["2022\u20132027"],"award-info":[{"award-number":["2022\u20132027"]}]},{"name":"CAPES-Print Fellowships (LRCC and SBSCC), Federal University of Para\u00edba, Brazil","award":["2020\u20132022"],"award-info":[{"award-number":["2020\u20132022"]}]},{"name":"CAPES-Print Fellowships (LRCC and SBSCC), Federal University of Para\u00edba, Brazil","award":["#35376"],"award-info":[{"award-number":["#35376"]}]},{"name":"CAPES-Print Fellowships (LRCC and SBSCC), Federal University of Para\u00edba, Brazil","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"CAPES-Print Fellowships (LRCC and SBSCC), Federal University of Para\u00edba, Brazil","award":["258000"],"award-info":[{"award-number":["258000"]}]},{"name":"CAPES-Print Fellowships (LRCC and SBSCC), Federal University of Para\u00edba, Brazil","award":["258259"],"award-info":[{"award-number":["258259"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and early stages are curable. However, a subset of PTCs shows an unusually aggressive phenotype with extensive lymph node metastasis and higher incidence of locoregional recurrence. In this study, we investigated a large cohort of PTC cases with an unusual aggressive phenotype using a high-throughput RNA sequencing (RNA-Seq) to identify differentially regulated genes associated with metastatic PTC. All metastatic PTC with mutated BRAF (V600E) but not BRAF wild-type expressed an up-regulation of R-Spondin Protein 4 (RSPO4) concomitant with an upregulation of genes involved in focal adhesion and cell-extracellular matrix signaling. Further immunohistochemistry validation confirmed the upregulation of these target genes in metastatic PTC cases. Preclinical studies using established PTC cell lines support that RSPO4 overexpression is associated with BRAF V600E mutation and is a critical upstream event that promote activation of kinases of focal adhesion signaling known to drive cancer cell locomotion and invasion. This finding opens up the potential of co-targeting B-Raf, RSPO and focal adhesion proteins as a pharmacological approach for aggressive BRAF V600E PTC.<\/jats:p>","DOI":"10.3390\/cells12010139","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:14:28Z","timestamp":1672370068000},"page":"139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of R-Spondin Gene Signature Predictive of Metastatic Progression in BRAFV600E-Positive Papillary Thyroid Cancer"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3742-2819","authenticated-orcid":false,"given":"Sabrina Daniela","family":"da Silva","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"},{"name":"Lady Davis Institute for Medical Research\/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e9goire B.","family":"Morand","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"},{"name":"Lady Davis Institute for Medical Research\/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, Luzerner Kantonsspital, 6004 Lucerne, Switzerland"},{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, University Hospital Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Diesel","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jefferson Muniz","family":"de Lima","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krikor","family":"Bijian","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research\/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senthilkumar","family":"Kailasam","sequence":"additional","affiliation":[{"name":"Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada"},{"name":"Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada"},{"name":"Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Bourque","sequence":"additional","affiliation":[{"name":"Canadian Centre for Computational Genomics, McGill University, Montreal, QC H3A 0G1, Canada"},{"name":"Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hier","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moulay A.","family":"Alaoui-Jamali","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research\/Segal Cancer Centre, Departments of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","unstructured":"Curado, M.P., Edwards, B., Shin, H.R., Storm, H., Ferlay, J., Heanue, M., and Boyle, P. (2007). Cancer Incidence in Five Continents, IARC Press, International Agency for Research on Cancer. IARC Scientific Publication No 160."},{"key":"ref_2","unstructured":"Statistics (2013). ACoC: Canadian Cancer Statistics 2013, Canadian Cancer Society. Available online: http:\/\/www.cancer.ca\/Reference\/?cceid=1700#ixzz2ZJNY0hbS."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1001\/jama.295.18.2164","article-title":"Increasing incidence of thyroid cancer in the United States, 1973\u20132002","volume":"295","author":"Davies","year":"2006","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1245\/s10434-013-2892-y","article-title":"The Acceleration in Papillary Thyroid Cancer Incidence Rates is Similar among Racial and Ethnic Groups in the United States","volume":"20","author":"Kaplan","year":"2013","journal-title":"Ann. Surg. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/bjc.2012.302","article-title":"A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas","volume":"107","author":"Dom","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1056\/NEJM199302253280807","article-title":"Management of a solitary thyroid nodule","volume":"328","author":"Mazzaferri","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1056\/NEJM199801293380506","article-title":"Papillary and follicular thyroid carcinoma","volume":"338","author":"Schlumberger","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s00268-018-4479-z","article-title":"Overall survival of papillary thyroid carcinoma patients: A single-institution long-term follow-up of 5897 patients","volume":"42","author":"Ito","year":"2018","journal-title":"World J. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"236","DOI":"10.14639\/0392-100X-N1412","article-title":"Predictive factors for recurrence of papillary thyroid carcinoma: Analysis of 4085 patients","volume":"41","author":"Kohler","year":"2021","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1089\/thy.2009.0110","article-title":"Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association (ATA) guidelines taskforce on thyroid nodules and differentiated thyroid cancer","volume":"19","author":"Cooper","year":"2009","journal-title":"Thyroid Off. J. Am. Thyroid Assoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1089\/thy.2016.0628","article-title":"American Thyroid Association guidelines on the management of thyroid nodules and differentiated thyroid cancer task force review and recommendation on the proposed renaming of encapsulated follicular variant papillary thyroid carcinoma without invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features","volume":"27","author":"Haugen","year":"2017","journal-title":"Thyroid Off. J. Am. Thyroid Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0140-6736(13)60109-9","article-title":"Progress in molecular-based management of differentiated thyroid cancer","volume":"381","author":"Xing","year":"2013","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"834456","DOI":"10.3389\/fendo.2022.834456","article-title":"Molecular Characterization of Thyroid Follicular Lesions in the Era of \u201cNext-Generation\u201d Techniques","volume":"13","author":"Rossi","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.cell.2014.09.050","article-title":"Integrated genomic characterization of papillary thyroid carcinoma","volume":"159","author":"Agrawal","year":"2014","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Boufraqech, M., and Nilubol, N. (2019). Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome. Cancers, 11.","DOI":"10.3390\/cancers11121988"},{"key":"ref_16","first-page":"309","article-title":"Insights into genetic and epigenetic determinants with impact on vitamin d signaling and cancer association studies: The case of thyroid cancer","volume":"4","author":"Morand","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10649","DOI":"10.1073\/pnas.1004934107","article-title":"B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression","volume":"107","author":"Nucera","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1210\/jc.2012-2104","article-title":"BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: A meta-analysis","volume":"97","author":"Li","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1200\/JCO.2014.56.8253","article-title":"Association between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer","volume":"33","author":"Xing","year":"2015","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_20","first-page":"1130","article-title":"Clinicopathological relevance of antithyroglobulin antibodies in low-risk papillary thyroid cancer","volume":"42","author":"Morand","year":"2017","journal-title":"Clin. Otolaryngol. Off. J. ENT-UK Off. J. Neth. Soc. Oto-Rhino-Laryngol. Cervico-Facial Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40463-022-00559-9","article-title":"Mutational status may supersede tumor size in predicting the presence of aggressive pathologic features in well differentiated thyroid cancer","volume":"51","author":"Morand","year":"2022","journal-title":"J. Otolaryngol.\u2014Head Neck Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1002\/cncr.33421","article-title":"Risk assessment for distant metastasis in differentiated thyroid cancer using molecular profiling: A matched case-control study","volume":"127","author":"Yip","year":"2021","journal-title":"Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"giz037","DOI":"10.1093\/gigascience\/giz037","article-title":"GenPipes: An open-source framework for distributed and scalable genomic analyses","volume":"8","author":"Bourgey","year":"2019","journal-title":"Gigascience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: Discovering splice junctions with RNA-Seq","volume":"25","author":"Trapnell","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1093\/bioinformatics\/btr355","article-title":"Identification of novel transcripts in annotated genomes using RNA-Seq","volume":"27","author":"Roberts","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_29","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bustin, S.A., Beaulieu, J.F., Huggett, J., Jaggi, R., Kibenge, F.S., Olsvik, P.A., Penning, L.C., and Toegel, S. (2010). MIQE precis: Practical implementation of minimum standard guidelines for fluorescence-based quantitative real-time PCR experiments. BMC Mol. Biol., 11.","DOI":"10.1186\/1471-2199-11-74"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/carcin\/bgaa017","article-title":"NDRG1 deficiency is associated with regional metastasis in oral cancer by inducing epithelial-mesenchymal transition","volume":"41","author":"Morand","year":"2020","journal-title":"Carcinogenesis"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"da Silva, S.D., Marchi, F.A., Su, J., Yang, L., Valverde, L., Hier, J., Bijian, K., Hier, M., Mlynarek, A., and Kowalski, L.P. (2021). Co-overexpression of TWIST1-CSF1 is a common event in metastatic oral cancer and drives biologically aggressive phenotype. Cancers, 13.","DOI":"10.3390\/cancers13010153"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ng1883","article-title":"The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia","volume":"38","author":"Blaydon","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nrc3792","article-title":"FAK in cancer: Mechanistic findings and clinical applications","volume":"14","author":"Sulzmaier","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s10585-012-9457-5","article-title":"Tumor microenvironment: A main actor in the metastasis process","volume":"29","author":"Spano","year":"2012","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/bjc.2012.592","article-title":"Matricellular proteins: Priming the tumour microenvironment for cancer development and metastasis","volume":"108","author":"Wong","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1056\/NEJMra1501993","article-title":"Biologic and clinical perspectives on thyroid cancer","volume":"375","author":"Fagin","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1016\/S0140-6736(16)30172-6","article-title":"Thyroid cancer","volume":"388","author":"Cabanillas","year":"2016","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the crime: Functions of cells recruited to the tumor microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1091\/mbc.e08-02-0187","article-title":"R-Spondin family members regulate the Wnt pathway by a common mechanism","volume":"19","author":"Kim","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11452","DOI":"10.1073\/pnas.1106083108","article-title":"R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt\/beta-catenin signaling","volume":"108","author":"Carmon","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nature10337","article-title":"Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling","volume":"476","author":"Barker","year":"2011","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/embor.2011.175","article-title":"LGR4 and LGR5 are R-spondin receptors mediating Wnt\/\u03b2-catenin and Wnt\/PCP signalling","volume":"12","author":"Glinka","year":"2011","journal-title":"EMBO Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"104123","DOI":"10.1016\/j.isci.2022.104123","article-title":"Canonical Wnt signaling induces focal adhesion and Integrin beta-1 endocytosis","volume":"25","author":"Morselli","year":"2022","journal-title":"iScience"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4326","DOI":"10.1038\/onc.2009.299","article-title":"Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage","volume":"28","author":"Provenzano","year":"2009","journal-title":"Oncogene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/j.cub.2009.07.069","article-title":"Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening","volume":"19","author":"Klein","year":"2009","journal-title":"Curr. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.ydbio.2014.07.023","article-title":"FAK is required for tension-dependent organization of collective cell movements in Xenopus mesendoderm","volume":"394","author":"Bjerke","year":"2014","journal-title":"Dev. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1083\/jcb.201609037","article-title":"Integrin-mediated mechanotransduction","volume":"215","author":"Sun","year":"2016","journal-title":"J. Cell Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/139\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:55:24Z","timestamp":1760147724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,29]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12010139"],"URL":"https:\/\/doi.org\/10.3390\/cells12010139","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,29]]}}}