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 TGFβ1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFβ/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions. Conclusion IQGAP3 knockdown suppressed the RAS-TGFβ signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Raw data of RNA sequence is available on GEO: GSE231642.

中文翻译：

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IQGAP3 信号传导介导肿瘤内功能异质性以促进恶性生长


背景 IQGAP3 在不同癌症中的表达升高表明 IQGAP3 在致癌作用中起关键作用。尽管 IQGAP3 被确定为增殖的胃干细胞因子和 RAS-ERK 通路的调节因子，但它如何驱动癌症生长仍不清楚。目的 我们确定了 IQGAP3 在胃癌 （GC） 发展和进展中的功能。设计 我们通过 RNA 测序研究了 IQGAP3 敲低在三种分子多样化的 GC 细胞系中引起的表型变化。体内肿瘤发生和肺转移测定证实 IQGAP3 是致癌信号传导的介质。进行空间分析以评估对照肿瘤和 IQGAP3 敲低肿瘤之间的瘤内转录和功能差异。结果 转录组学分析显示，IQGAP3 抑制通过磷酸化阻断减弱信号转导网络，例如 KRAS 信号传导。IQGAP3 敲低与 MEK/ERK 信号相关生长因子（包括 TGFβ1）的显着抑制相关，伴随着预测肿瘤微环境形成受损和转移潜力降低的基因特征。涉及 IQGAP3 敲低细胞的异种移植物在免疫缺陷小鼠中显示出减弱的肿瘤发生和肺转移。因此，免疫荧光染色显示 TGFβ/SMAD 信号传导和 αSMA 阳性基质细胞显着减少;数字空间分析表明，IQGAP3 对于两个表型多样化的细胞亚群的形成是必不可少的，它们在促进致癌功能方面发挥着关键但不同的作用。结论 IQGAP3 敲低抑制了 RAS-TGFβ 信号转导串扰，导致肿瘤微环境显著减少。 特别是，IQGAP3 维持癌细胞的功能异质性以增强恶性生长。因此，IQGAP3 是 GC 中高度相关的治疗靶点。数据可根据合理要求提供。与研究相关的所有数据都包含在文章中或作为补充信息上传。RNA 序列的原始数据可在 GEO： GSE231642 上获得。