Puig Marta, Lugo Roberto, Gabasa Marta, Giménez Alícia, Velásquez Adriana, Galgoczy Roland, Ramírez Josep, Gómez-Caro Abel, Busnadiego Óscar, Rodríguez-Pascual Fernando, Gascón Pere, Reguart Noemí, Alcaraz Jordi
Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. Medical Oncology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Mol Cancer Res. 2015 Jan;13(1):161-73. doi: 10.1158/1541-7786.MCR-14-0155. Epub 2014 Oct 3.
The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by β1 integrin mechano-sensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs.
This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.
肿瘤相关成纤维细胞（TAF）在非小细胞肺癌（NSCLC）进展中的关键作用现已明确。然而，由于对其积累背后的亚型特异性机制缺乏了解，针对TAF的治疗方法有限。在此，剖析了驱动非小细胞肺癌主要亚型腺癌（ADC）和鳞状细胞癌（SCC）中TAF积累的机械性（即基质硬度）和可溶性促有丝分裂信号。将成纤维细胞培养在经工程处理以在不同血清浓度下表现出正常或肿瘤样硬度的基质上，并阐明关键的调节过程。在来自非恶性组织的对照成纤维细胞中，单独的基质硬化增加了成纤维细胞的积累，并且这种机械效应在高达0.5%血清时占主导或与可溶性生长因子相当。基质硬度的刺激信号由β1整合素通过FAK（pY397）的机械传感驱动，并与转录后驱动的β1整合素表达增加相关。在TAF中也观察到了后一种机械调节回路，但以亚型特异性方式，因为SCC-TAF比ADC-TAF表现出更高的FAK（pY397）、β1表达和ERK1/2（pT202/Y204）。此外，与ADC-TAF（10%-20%）相比，基质硬化在SCC-TAF中诱导了更大的TAF积累（>50%）。相反，SCC-TAF在很大程度上对血清脱敏，而ADC-TAF仅对高血清浓度有反应。这些发现提供了非小细胞肺癌TAF积累的亚型特异性调节的首个证据。此外，这些数据支持旨在恢复正常肺弹性和/或β1整合素依赖性机械调节的疗法可能对SCC-TAF有效，而抑制基质生长因子信号传导可能对ADC-TAF有效。
本研究揭示了肺癌两种主要亚型中肿瘤支持性成纤维细胞异常积累的不同机制，这将有助于开发针对这些细胞的个性化疗法。
