Background

The tumor-microenvironment (TME) represents an attractive therapeutic target in NSCLC and plays an important role for efficacy of cancer therapeutics. We hypothesized that upregulation of collagen synthesis might be associated with adverse outcome in NSCLC. Literature evidence suggests that renin-angiotensin system inhibitors (RASi) decrease collagen deposition. Therefore, we aimed to explore the prognostic role of RASi intake and their influence on the TME in NSCLC.

Methods

Four publicly available datasets were used to evaluate the impact of key enzymes involved in collagen biosynthesis. To investigate the influence of RASi intake on the TME and prognosis we evaluated a cohort of metastatic NSCLC patients and performed histopathological characterization of the TME. A three-dimensional microtissue in vitro model was developed to define the impact of RASi on collagen synthesis.

Results

Expression of three genes of the collagen synthesis pathway, ALDH18A1, PLOD2 and P4HA1, was upregulated in NSCLC compared to normal lung tissue and linked to shortened overall survival in all investigated cohorts. Together, these genes formed a ‘Collagen Signature’ which represents an independent unfavourable prognostic factor in two NSCLC cohorts and was linked to alterations of the extracellular matrix deposition and cell cycle pathways. In the cohort of metastatic NSCLC, RASi intake was linked to improved overall response rate and survival. Exploratory in vitro experiments revealed that RASi led to a dose dependent reduction of collagen deposition and degradation of three-dimensional lung cancer cell spheroids.

Conclusion

We demonstrate that collagen synthesis is a key upregulated process in the NSCLC TME and its transcriptional readout, the three gene Collagen Signature is independently associated with poor outcome. Pharmacological targeting of this pathways e.g. by RASi bears potential of improving outcome in NSCLC.

中文翻译：

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失调的谷氨酸盐转化为前胶原蛋白与肺癌的不良结果相关，并且可能被肾素-血管紧张素-醛固酮系统 (RAS) 抑制靶向

背景

肿瘤微环境 (TME) 是 NSCLC 中一个有吸引力的治疗靶点，对癌症治疗的疗效起着重要作用。我们假设胶原合成的上调可能与 NSCLC 的不良结果相关。文献证据表明肾素-血管紧张素系统抑制剂 (RASi) 可减少胶原沉积。因此，我们旨在探讨 RASi 摄入量的预后作用及其对 NSCLC 中 TME 的影响。

方法

四个公开可用的数据集用于评估参与胶原蛋白生物合成的关键酶的影响。为了研究 RASi 摄入对 TME 和预后的影响，我们评估了一组转移性 NSCLC 患者并进行了 TME 的组织病理学表征。开发了一个三维微组织体外模型来定义 RASi 对胶原蛋白合成的影响。

结果

与正常肺组织相比，胶原合成途径的三个基因ALDH18A1、PLOD2和P4HA1 的表达在 NSCLC 中上调，并与所有研究队列中的总生存期缩短有关。这些基因共同形成了一个“胶原特征”，它代表了两个 NSCLC 队列中的一个独立的不利预后因素，并且与细胞外基质沉积和细胞周期途径的改变有关。在转移性 NSCLC 队列中，RASi 摄入量与总体反应率和生存率的提高有关。体外探索性实验表明，RASi 导致胶原沉积和三维肺癌细胞球体降解的剂量依赖性减少。

结论

我们证明胶原合成是 NSCLC TME 及其转录读数中的关键上调过程，三个基因胶原特征与不良结果独立相关。该途径的药理学靶向，例如通过 RASi 具有改善非小细胞肺癌预后的潜力。