GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma

Abstract

Efficacious therapeutic approaches are urgently needed to improve outcomes in patients with oesophageal adenocarcinoma (OAC). However, oncogenic drivers amenable to targeted therapy are limited and their functional characterisation is essential. Among few targeted therapies available, anti-human epidermal growth factor receptor 2 (HER2) therapy showed only modest benefit for patients with OAC. Herein, we investigated the potential oncogenic role of growth factor receptor bound protein 7 (GRB7), which is reported to be co-amplified with HER2 (ERBB2) in OAC. GRB7 was highly expressed in 15% of OAC tumours, not all of which could be explained by co-amplification with HER2, and was associated with a trend for poorer overall survival. Knockdown of GRB7 decreased proliferation and clonogenic survival, and induced apoptosis. Reverse phase protein array (RPPA) analyses revealed a role for PI3K, mammalian target of rapamycin (mTOR), MAPK, and receptor tyrosine kinase signalling in the oncogenic action of GRB7. Furthermore, the GRB7 and HER2 high-expressing OAC cell line Eso26 showed reduced cell proliferation upon GRB7 knockdown but was insensitive to HER2 inhibition by trastuzumab. Consistent with this, GRB7 knockdown in vivo with an inducible shRNA significantly inhibited tumour growth in cell line xenografts. HER2 expression did not predict sensitivity to trastuzumab, with Eso26 xenografts remaining refractory to trastuzumab treatment. Taken together, our study provides strong evidence for an oncogenic role for GRB7 in OAC and suggests that targeting GRB7 may be a potential therapeutic strategy for this cancer.

C5b-9 Membrane Attack Complex Formation and Extracellular Vesicle Shedding in Barrett’s Esophagus and Esophageal Adenocarcinoma

“…To evaluate esophageal tissue C9 and C5b-9 levels during the sequence normal epithelium (NE)-BE-EAC, we generated and stained a tissue microarray (TMA) from archival esophageal tissue samples from patients undergoing investigation for BE or suspected EAC, and also stained a previously established TMA of EAC cases ( 17 , 18 ). A multiplex immunohistofluorescence (mIHF) method was developed to enable co-staining and co-localization of C9 and C5b9, as detailed in Methods.…”

“…Two tissue microarrays were analyzed in this study. Information on the EAC tissue microarray was previous published ( 17 , 18 ). A BE tissue microarray was generated from formalin-fixed, paraffin-embedded archival esophageal tissue samples retrieved from 89 patients at Envoi Pathology, Brisbane, Australia.…”

Up-regulated GRB7 protein in gastric cancer cells correlates with clinical properties and increases proliferation and stem cell properties

“…GRB7 has been found to have an important growth promoting function in human breast cancer cell lines, and inhibition of GRB7 will reduce the motility of breast cancer cells and promote cell death ( 18 , 19 ). Overexpression of GRB7 in cervical cancer has been found to promote cervical cancer cell invasion and inhibit cell apoptosis, while knockdown of GRB7 in esophageal adenocarcinoma reduces proliferation and induces apoptosis ( 20 , 21 ). It can be seen that a variety of tumor models have verified the important role of GRB7 molecules in the malignant process of tumors.…”

La proteína 7 unida al receptor del factor de crecimiento (GRB7) en cáncer de mama

“…20,22 Se ha descrito una variante truncada de GRB7 (GRB7v) de 447 aminoácidos, la cual es codificada por un transcrito de 1,667 con solo 13 exones en cánceres de esófago23 y de ovario. 24 Los miembros de la familia a la que pertenece GRB7 tienen una estructura altamente conservada. GRB7 es reconocida como una proteína multidominio 25 conformada por tres regiones: una amino terminal que presenta un dominio rico en prolina, la región central GM (por Grb y Mig) y…”