PO.TB10.12 · 肿瘤生物学
肺腺癌中胶原更新以纤维生成为主，而肺鳞状细胞癌中以纤维溶解为主
Collagen turnover is dominated by fibrogenesis in lung adenocarcinoma and fibrolysis in lung squamous cell carcinomas
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摘要 Abstract
中文摘要
非小细胞肺癌（NSCLC）的肿瘤间质高度促结缔组织增生/纤维化，正逐渐成为肿瘤进展、免疫逃逸和治疗耐药的关键调控因素。肿瘤纤维化以胶原的异常蓄积为特征。然而，我们对胶原更新及其对组织学亚型潜在依赖性的认识十分有限。在此，我们结合转录谱分析和基于ELISA的胶原片段新表位检测，分析了肿瘤相关成纤维细胞（TAFs）以及来自NSCLC主要组织学亚型——肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）——肿瘤样本中的胶原生成（纤维生成）和降解（纤维溶解）。在培养中，LUSC-TAFs表现出增强的胶原更新，生成标志物（exPRO-C1、PRO-C3和PRO-C6）和降解标志物（C1M、C3M、C6M）均升高。与之一致，LUSC-TAFs的纤维状胶原和胶原溶解性MMPs的RNA水平均较高，而TIMP-1（主要胶原溶解性MMPs的天然抑制剂）在RNA和分泌蛋白水平呈现相反的模式。在bulk RNA-seq数据（TCGA）和手术标本TMAs的组织学分析中，观察到一致的组织学亚型依赖性胶原更新特征。我们的结果表明，LUAD中通过TIMP-1生成增加和胶原溶解性MMPs水平降低而倾向于纤维生成，而LUSC中通过胶原溶解性MMPs（尤其是MMP1）生成增加和TIMP-1生成减少而以纤维溶解为主。从机制上讲，TGF-beta1是肿瘤纤维化的主要驱动因素，在正常成纤维细胞中敲低SMAD2或SMAD3——以模拟先前报道的肺TAFs中组织学亚型特异性的SMAD2/3表达模式（Ikemori等，Cancer Res 2020）——足以重现LUAD和LUSC之间胶原更新的关键差异特征。综上，这些数据揭示了NSCLC中相反的胶原更新程序，其中LUAD主要为纤维生成型，而LUSC主要通过组织学亚型依赖性的调控过程呈纤维溶解型。靶向这些分化的程序可能有助于逆转病理性纤维化并改善NSCLC对化疗和/或免疫治疗的应答。
查看英文原文 English abstract
The tumor stroma in non-small cell lung cancer (NSCLC) is highly desmoplastic/fibrotic and is emerging as a key regulator of tumor progression, immune evasion and therapy resistance. Tumor fibrosis is characterized by the aberrant accumulation of collagen. However, our understanding of collagen turnover and its potential dependence on the histologic subtype is very limited. Here, we combined transcriptional profiling and ELISA-based assays for neoepitope collagen fragments to analyze collagen production (fibrogenesis) and degradation (fibrolysis) in tumor-associated fibroblasts (TAFs) and in tumor samples from the major NSCLC histologic subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In culture, LUSC-TAFs exhibited enhanced collagen turnover with increased markers of both production (exPRO-C1, PRO-C3 and PRO-C6) and degradation (C1M, C3M, C6M). Consistently, LUSC-TAFs exhibited higher RNA levels of both fibrillar collagens and collagenolytic MMPs, whereas TIMP-1 (a natural inhibitor of major collagenolytic MMPs) showed opposite patterns at the RNA and secreted protein levels. Consistent hystotype-dependent collagen-turnover signatures were observed in bulk RNA-seq data (TCGA) and in histologic analyses of TMAs from surgical specimens. Our results indicate that fibrogenesis is favored in LUAD through increased production of TIMP-1 and lower levels of collagenolytic MMPs, whereas fibrolysis is dominant in LUSC through increased production of collagenolytic MMPs (notably MMP1) and reduced production of TIMP-1. Mechanistically, TGF-beta1 is a major driver of tumor fibrosis, and knocking-down SMAD2 or SMAD3 in normal fibroblasts -to mimic previously reported histotype-specific SMAD2/3 expression patterns in lung TAFs (Ikemori et al, Cancer Res 2020) - was sufficient to recapitulate key differential features of collagen turnover between LUAD and LUSC. Together, these data reveal opposite collagen-turnover programs in NSCLC, in which LUAD are predominantly fibrogenic, whereas LUSC are largely fibrolytic through histotype-dependent regulatory processes. Targeting these divergent programs may help revert pathologic fibrosis and improve responses to chemotherapy and/or immunotherapy in NSCLC.
利益披露 Disclosure
V. Batto, None..
M. Arshakyan, None..
E. Almici, None..
M. Karsdal, None..
J. Alcaraz, None.