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

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.

Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

“…Beside the role of somatostatin receptors, the role of genes involved in epithelial-mesenchymal transition, cell proliferation, and cell signaling was previously reported [ 26 ]. Transcriptomic groups of somatotroph PitNETs differed in the expression of genes related to epithelial-mesenchymal transition (EMT) that have a proven role in acromegaly, including CDH1 [ 27 , 28 ], SNAI2 [ 29 ], FLNA [ 30 ], ARRB1 [ 31 , 32 ], RORC [ 33 ], and ESRP1 [ 28 ], but also in other genes with an important role in EMT including CDH2 , CDH3 , CDH11 , CTNNB1 , CLDN1 , CLDN3 , CLDN4 , CLDN9 , and ZAEB1 ( Figure 4 A). Differences between transcriptomic groups were also observed in expression levels of proliferation-related genes CCND1 [ 34 ], CDKN1B [ 27 ], and MKI67 [ 35 ] and genes involved in cell signaling TGFB1 [ 36 ] and STAT3 [ 37 ] that all have a reported role in acromegaly patients’ outcome ( Figure 4 B).…”

“…Importantly, striking differences in the expression of CDH1 were observed between transcriptomic groups with the highest expression in group 2 and the lowest in group 3. The expression profile of other genes that were previously shown to be related to SRLs response [ 27 , 28 , 31 , 33 , 46 ] suggests also that tumors in transcriptomic group 2 may be the most sensitive to somatostatin analogs. They have a favorable pattern of gene expression—those related to EMT (high RORC and ESRP1 and low ARRB1 (β-arrestin)) as well as SSTR5 (the highest expression among subtypes), MKI67 (low expression), and CDKN1B (high level).…”

Transcriptomic classification of pituitary neuroendocrine tumors causing acromegaly

“…Importantly, striking differences in the expression of CDH1 were observed between transcriptomic groups with the highest expression in group 2 and the lowest in group 3. The expression profile of other genes, that were previously shown to be related to SRLs response, (Kiseljak-Vassiliades et al, 2015;Chauvet et al, 2016;Gatto et al, 2016;Gil et al, 2022;Iacovazzo et al, 2016) suggests also that tumors in transcriptomic group 2 may be the most sensitive to somatostatin analogs. They have a favorable pattern of gene expressionthose related to EMT (high RORC and ESRP1 and low ARRB1 (β-arrestin)) as well as SSTR5 (the highest expression among subtypes), MKI67 (low expression) and CDKN1B (high level).…”

“…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).…”

Delving into Acromegaly

“…Several research groups have advocated the use of biomarkers to identify therapeutic responses ideally even before starting treatment, thereby allowing for a more targeted therapeutic approach [ 17 , 18 ]. Gil et al, for instance, analyzed resistance against SSA and the expression of genes related to E-cadherin loss and epithelial–mesenchymal transition [ 19 ]. They found a heterogenous expression pattern, but also an indication of a role of RORC in SSA response with a higher probability of complete response in pre-treated patients expressing high levels of RORC .…”