IQGAP3 signalling mediates intratumoral functional heterogeneity to enhance malignant growth

Menée à l'aide de lignées cellulaires de cancer gastrique et d'un modèle murin de métastases pulmonaires, cette étude met en évidence un mécanisme par lequel la protéine IQGAP3 augmente la croissance tumorale en maintenant l'hétérogénéité fonctionnelle des cellules cancéreuses

Résumé en anglais

Background : The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear.

Objective : We define the function of IQGAP3 in gastric cancer (GC) development and progression.

Design : We studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours.

Results : Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGF