Decoupling the Mechanobiology of Neutrophil Extracellular Traps (NETs) in Tumor Metastasis

阿尔温德·拉塞卡兰 摘要 肿瘤微环境（TME）和周围基质的机械刚度是一个重要的因素。 影响细胞功能的物理参数。增加的细胞外基质（ECM）硬度是 开始被认为是肿瘤发生的驱动因素， 介导从休眠状态到恶性状态的转变。然而，理解最初的 导致基质刚性的病理前放大的机制仍在发展。 中性粒细胞形成先天免疫系统中最丰富的细胞群，代表50- 60%的循环白色血细胞，是炎症期间的第一道防线， 感染在某些条件下，激活的中性粒细胞会发生程序性细胞死亡 通过释放去致密的染色质，组蛋白和DNA到它们周围的ECM中，形成三个- 蛋白质网络结构称为神经细胞外陷阱（NETs）。最近的证据 这表明在肿瘤周围形成的NETs可能与肿瘤直接相关， 转移进展。然而，NET的确切机制和信号通路 与肿瘤细胞和基质的相互作用仍在研究中。 本项目建议书的主要目标是破译机械生物学的影响， NET，即调节组织的机械性能（如刚度和孔隙度）， NET的形成，特别是在肿瘤转移的背景下。基本假设 该建议的一个重要方面是，在肿瘤周围积聚的NET与ECM中存在的蛋白质结合， 并使基质充分膨胀以诱导与肿瘤相关的下游生物效应 生长和入侵。该项目的长期目标是了解机械生物学 疾病过程中NET的组织和调节。更好地理解这一概念 可能对开发合适的治疗药物具有范式转移的意义， 干预措施，不仅在肿瘤转移的背景下，而且对发病机制， 其他传染病和自身免疫性疾病。

Arvind Chandrasekaran Abstract Mechanical rigidity of a tumor microenvironment (TME) and the surrounding stroma is an important physical parameter that affects cellular functions. Increased Extracellular Matrix (ECM) stiffness is beginning to be considered as a driving factor in tumor initiation, contributing significantly in mediating the transition from dormant to malignant states. However, understanding of the initial mechanisms leading to the pre-pathological amplification in matrix rigidity is still evolving. Neutrophils form the most abundant cell population of the innate immune system, representing 50– 60% of circulating white blood cells and are the first line of defense during inflammation and infection. Under certain conditions, activated neutrophils undergo a form of programmed cell death by releasing decondensed chromatin, histones and DNA into their surrounding ECM, forming three- dimensional protein web structures called Neutrophil Extracellular Traps (NETs). Recent evidences suggest that NETs that are formed around a tumor could be directly associated with tumor metastasis progression. However, the exact mechanisms and the signaling pathways of NETs interactions with the tumor cells and the stroma are still under research. The primary objective of this project proposal is to decipher the mechanobiological implications of NETs, i.e regulation of the mechanical properties of the tissues (such as stiffness and porosity) due to the formation of NETs, specifically in the context of tumor metastasis. The fundamental hypothesis of this proposal is that NETs accumulating around a tumor bind to the proteins present in the ECM, and stiffen the matrix sufficiently enough to induce downstream biological effects related to tumor growth and invasion. The long-term goal of this project is to understand the mechanobiological organization and regulation of NETs in disease processes. A better comprehension of this concept could have paradigm-shifting implications with respect to the development of suitable therapeutic interventions, not just within the context of tumor metastasis but also towards the pathogenesis of other infectious and autoimmune diseases.