Implications of Heterogeneity of Epithelial-Mesenchymal States in Acromegaly Therapeutic Pharmacologic Response.

Cristina Lamas,Betina Biagetti,Cristina Carrato,Isabel Salinas,Montserrat Marqués‐Pamies ,Mireia Jordà,Rosa Cámara,Joan Gil,Antonio Picón ,Elena Valassi,Cristina Hostalot,Mónica Marazuela,Manel Puig‐Domingo ,Araceli García‐Martínez ,Guillermo Serra,Ignacio Bernabéu ,Andreu Simó-Servat,Helena Rodríguez-Lloveras,Susan M Webb,Carmen Fajardo‐Montañana

doi:10.3390/biomedicines10020460

Abstract

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.

Highlights

Is a rare disorder mainly caused by a growth hormone (GH)-producing pituitary tumor
We analyzed the expression of a subset of epithelial-mesenchymal transition (EMT)-related genes, including the epithelial marker ESRP1; the mesenchymal markers vimentin, N-cadherin, SNAI1, SNAI2, and TWIST1; and RORC, which previously has been related to Ecadherin and EMT in acromegaly [31]
The correlations we found in GH-producing tumors between EMT-related genes could denote a coordinated gene program for EMT in these adenomas as well, as it occurs in solid malignancies [38]

Summary

Introduction

Is a rare disorder mainly caused by a growth hormone (GH)-producing pituitary tumor. First-line treatment includes endoscopic surgery [2], but the surgical cure rate is around 50% in patients presenting extrasellar growth [3]. In those cases, patients receive adjuvant therapy with first-generation somatostatin receptor ligands (SRLs) [4,5]. The response to SRLs varies widely among the different studies (success rates of 20–40%) [5,6,7], and the resulting comorbidities of an uncontrolled disease severely impacts patients’ lives [1,8,9]. We analyzed almost all previously reported molecular markers in a large series of GH-producing pituitary tumors, and confirmed that the progressive loss of response to SRLs was associated with the loss of

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Conclusion