Epithelial–Mesenchymal Transition in the Resistance to Somatostatin Receptor Ligands in Acromegaly

Abstract

Epithelial-mesenchymal transition (EMT) is a dynamic process by which epithelial cells loss their phenotype and acquire mesenchymal traits, including increased migratory and invasive capacities. EMT is involved in physiological processes, such as embryogenesis and wound healing, and in pathological processes such as cancer, playing a pivotal role in tumor progression and metastasis. Pituitary tumors, although typically benign, can be locally invasive. Different studies have shown the association of EMT with increased tumor size and invasion in pituitary tumors, and in particular with a poor response to Somatostatin Receptor Ligands (SRLs) treatment in GH-producing pituitary tumors, the main cause of acromegaly. This review will summarize the current knowledge regarding EMT and SRLs resistance in acromegaly and, based on this relation, will suggest new biomarkers and possible therapies to SRLs resistant tumors.

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

“…EMT plays a fundamental role in the development of multiple tissues, including the pituitary gland [ 32 , 33 ]. This physiological process, which is aberrantly used by tumor cells, also occurs in pituitary tumors [ 34 , 35 ], especially in acromegaly [ 18 , 31 ], where EMT has been related to the response to SRLs [ 12 , 19 , 22 ]. Here, we further investigated EMT in GH-producing tumors, and found that most of them exhibited hybrid intermediate epithelial/mesenchymal expression profiles, which could be explained by the activation of alternative EMT programs and the progression of individual cells to different states along the EMT spectrum.…”

“…Certainly, this is not the only EMT-related mechanism involved in resistance to SRLs in acromegaly, but a negative EMT-related effect upon responsiveness to SRLs may have been present with variable intensity in some of the NR patients. Elucidation of the mechanistic of this phenomenon also would be of much interest, as targeted therapies aiming to deactivate it would re-sensitize GH-producing tumors toward SRL responsiveness [ 22 ].…”

“…This mechanism allows epithelial cells to acquire invasive properties [ 16 ]. Several works have demonstrated the association of EMT [ 17 , 18 ], and specifically the loss of E-cadherin [ 19 , 20 , 21 ], with larger tumors and invasion, as well as lack of response to SRLs in GH-producing tumors [ 22 ]. Epithelial Splicing Regulator 1 ( ESRP1 ) has been proposed to be a master regulator of EMT in somatotropinomas by modifying splicing programs [ 17 , 18 ].…”

Transcriptomic classification of pituitary neuroendocrine tumors causing acromegaly

“…Aberrant gene expression was previously shown to be involved in acromegaly patients' outcome and response to SRLs. Beside the role of somatostatin receptors, the role of genes involved in epithelialmesenchymal transition, cell proliferation and cell signaling was previously reported (Gil et al, 2021a) Transcriptomic groups of somatotroph PitNETs differed in the expression of genes related to epithelialmesenchymal transition (EMT) that have proven role in acromegaly including CDH1 (Kiseljak-Vassiliades et al, 2015;Chauvet et al, 2016), SNAI2 (Mendes et al, 2018), FLNA (Coelho et al, 2019), ARRB1 (Gatto et al, 2016(Gatto et al, , 2013, RORC (Gil et al, 2022) and ESRP1 (Chauvet et al, 2016) but also in other genes with an important role in EMT including CDH2, CDH3, CDH11, CTNNB1, CLDN1, CLDN3, CLDN4, CLDN9 and ZAEB1 (Figure 4A). Differences between transcriptomic groups were also observed in expression levels of proliferation-related genes CCND1 (Vitali et al, 2014), CDKN1B (Kiseljak-Vassiliades et al, 2015) and MKI67 (Gil et al, 2021b) and genes involved in cell signaling TGFB1 and STAT3 (Zhou et al, 2015) that all have a reported role in acromegaly patients outcome (Figure 3B).…”

Data mining analyses for precision medicine in acromegaly: a proof of concept

“…Different factors, such as age and sex 13 , 14 , radiologic information such as T2-weighted MRI signal intensity 15 , and histopathologic data such as granularity pattern 16 , 17 are related to therapeutic outcomes. Tumor expression of SSTR2 and other molecules have offered additional insights in relation to treatment response 11 , 18 , although some studies have shown controversial results 19 .…”