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

Arvind Chandrasekaran 摘要 肿瘤微环境(TME)和周围间质的机械刚性是一个重要的 影响细胞功能的物理参数。细胞外基质(ECM)硬度增加 开始被认为是肿瘤发生的驱动因素，在 调节从休眠状态到恶性状态的转变。然而，对最初的理解 导致病变前基质刚性放大的机制仍在发展中。 中性粒细胞构成了先天免疫系统中最丰富的细胞群，代表了50- 60%的循环中的白细胞，是炎症和疾病期间的第一道防线 感染。在某些条件下，激活的中性粒细胞会经历一种程序性细胞死亡。 通过释放去浓缩的染色质、组蛋白和DNA到它们周围的细胞外基质中，形成三种- 三维蛋白质网状结构称为中性粒细胞胞外陷阱(Net)。最近的证据 提示肿瘤周围形成的Net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 与肿瘤细胞和间质的相互作用仍在研究中。 该项目提案的主要目标是破译 Net，即对组织的机械特性(如硬度和孔隙率)的调节 Net的形成，特别是在肿瘤转移的背景下。基本假设 这一提议的核心是，聚集在肿瘤周围的网络与细胞外基质中存在的蛋白质结合， 并使基质足够坚硬，从而引起与肿瘤相关的下游生物效应 增长和入侵。这个项目的长期目标是了解机械生物学 疾病过程中网络的组织和管理。更好地理解这一概念 可能会对开发合适的治疗方法产生范式转换的影响 干预措施，不仅在肿瘤转移的背景下，而且还针对 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.