1fa86dd26c08691ea94414f9fc6607a3 pmc_8962441.pdf 927db5e9d0a8de4fe44ad19b2153bde563bf6410 pmc_8962441.pdf 6ab50dc2c753fb6054060c7afd9ead22d3d09008ef4d5895f813257f4fa2ca20 pmc_8962441.pdf Title: Implications of Heterogeneity of Epithelial-Mesenchymal States in Acromegaly Therapeutic Pharmacologic Response Subject: Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making. Keywords: epithelial-mesenchymal transition; acromegaly; somatostatin receptor ligands (SRLs); somatostatin analogs (SSAs); RORC; SNAI1; presurgical SRLs treatment; pituitary tumors Author: Joan Gil, Montserrat Marques-Pamies, Elena Valassi, Araceli García-Martínez, Guillermo Serra, Cristina Hostalot, Carmen Fajardo-Montañana, Cristina Carrato, Ignacio Bernabeu, Mónica Marazuela, Helena Rodríguez-Lloveras, Rosa Cámara, Isabel Salinas, Cristina Lamas, Betina Biagetti, Andreu Simó-Servat, Susan M. Webb, Antonio Picó, Mireia Jordà and Manel Puig-Domingo Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Feb 22 02:24:16 2022 CET ModDate: Tue Feb 22 02:30:32 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 26135543 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CMFVHJ+VnURWPalladioL Type 1 Custom yes yes no 10 0 UPBLEX+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 CCQQII+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 HLQTQU+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 HSNKGA+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 36 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 40 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 44 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 56 0 YFFKLH+CMSY10 Type 1 Builtin yes yes no 81 0 EOWADA+EURM10 Type 1 Builtin yes yes no 99 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-05-20 02:23:43 CEST RepresentationInformation: pmc_8962441.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-04-26 17:58:43 CEST Size: 26135543 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 442 FreeObjects: 19 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4923ab24 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Children: Item: Title: Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: DNA and RNA Isolation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: E-Cadherin Promoter Methylation Assessment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Reverse Transcription and Quantitative Polymerase Chain Reaction (RT-qPCR) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: RORC Immunohistochemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Biochemical and Hormonal Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: E-Cadherin Expression Did Not Correlate with Promoter Methylation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: SRLs Treatment before Surgery Affected the Expression of Some EMT-Related Genes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Association of EMT Markers with Clinical Variables Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: GH-Producing Tumors Showed Different Intermediate EMT States with No Association with SRL Response Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Association of SNAI1 and RORC Expression with SRL Response Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Info: Title: Implications of Heterogeneity of Epithelial-Mesenchymal States in Acromegaly Therapeutic Pharmacologic Response Author: Joan Gil, Montserrat Marques-Pamies, Elena Valassi, Araceli García-Martínez, Guillermo Serra, Cristina Hostalot, Carmen Fajardo-Montañana, Cristina Carrato, Ignacio Bernabeu, Mónica Marazuela, Helena Rodríguez-Lloveras, Rosa Cámara, Isabel Salinas, Cristina Lamas, Betina Biagetti, Andreu Simó-Servat, Susan M. Webb, Antonio Picó, Mireia Jordà and Manel Puig-Domingo Subject: Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making. Keywords: epithelial-mesenchymal transition; acromegaly; somatostatin receptor ligands (SRLs); somatostatin analogs (SSAs); RORC; SNAI1; presurgical SRLs treatment; pituitary tumors Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Feb 22 02:24:16 CET 2022 ModDate: Tue Feb 22 02:30:32 CET 2022 ID: 0x3a3b7f9f4d22b5dcec073452f64d89af, 0x3a3b7f9f4d22b5dcec073452f64d89af Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: YFFKLH+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: YFFKLH+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: EOWADA+EURM10 FontSubset: true FirstChar: 11 LastChar: 31 FontDescriptor: FontName: EOWADA+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: CCQQII+URWPalladioL-Roma FontSubset: true FirstChar: 1 LastChar: 252 FontDescriptor: FontName: CCQQII+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true 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