Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
Oncogene. 2023 Feb;42(7):491-500. doi: 10.1038/s41388-022-02513-5. Epub 2022 Nov 10.
Pancreatic stellate cells (PSCs) are key to the treatment-refractory desmoplastic phenotype of pancreatic ductal adenocarcinoma (PDAC) and have received considerable attention as a stromal target for cancer therapy. This approach demands detailed understanding of their pro- and anti-tumourigenic effects. Interrogating PSC-cancer cell interactions in 3D models, we identified nuclear FGFR1 as critical for PSC-led invasion of cancer cells. ChIP-seq analysis of FGFR1 in PSCs revealed a number of FGFR1 interaction sites within the genome, notably NRG1, which encodes the ERBB ligand Neuregulin. We show that nuclear FGFR1 regulates transcription of NRG1, which in turn acts in autocrine fashion through an ERBB2/4 heterodimer to promote invasion. In support of this, recombinant NRG1 in 3D model systems rescued the loss of invasion incurred by FGFR inhibition. In vivo we demonstrate that, while FGFR inhibition does not affect the growth of pancreatic tumours in mice, local invasion into the pancreas is reduced. Thus, FGFR and NRG1 may present new stromal targets for PDAC therapy.
胰腺星状细胞（PSCs）是胰腺导管腺癌（PDAC）治疗抵抗性纤维母细胞表型的关键，并且作为癌症治疗的基质靶点受到了相当多的关注。这种方法需要详细了解其促肿瘤和抗肿瘤作用。通过在 3D 模型中分析 PSC-癌细胞相互作用，我们发现核 FGFR1 对于 PSC 引导的癌细胞侵袭至关重要。对 PSCs 中 FGFR1 的 ChIP-seq 分析揭示了基因组内的多个 FGFR1 相互作用位点，特别是编码 ERBB 配体神经调节蛋白的 NRG1。我们表明，核 FGFR1 调节 NRG1 的转录，NRG1 反过来通过 ERBB2/4 异二聚体以自分泌方式发挥作用，促进侵袭。支持这一观点的是，在 3D 模型系统中，重组 NRG1 挽救了 FGFR 抑制引起的侵袭丧失。在体内，我们证明虽然 FGFR 抑制不会影响小鼠胰腺肿瘤的生长，但局部侵袭到胰腺的程度降低。因此，FGFR 和 NRG1 可能为 PDAC 治疗提供新的基质靶点。
