Cell-in-cell调变肿瘤免疫微环境的研究

Cell-in-cell structures (CICs) refer to the unusual structures with one or more viable cells existing inside another one, which occur in most species ranging from lower organisms to mammals，whose biological significance has attracted more and more attention. Tumor microenvironment is the most common area where CICs form in the human body, and the interactions between CICs and tumor microenvironment are becoming new hotspots in life sciences. Our previous study showed that some tumor cells could acquire the ability to form CICs under stressors such as lack of oxygen or nutrient scarcity, and the subsequent triggering of physiological and pathological processes. We speculate that CICs forming ability is determined by mammalian cell’s primitivity and evolutionary throwback, which will generate unexpected biological effect. Outer tumor cells can disassemble and utilize inner cells’ component for survival or acquiring completely new biological features after CICs have formed under stress condition. This process is considered an important promoter for the modulation of immune microenvironment. By developing a tumor immune microenvironment model with different stressors in vitro, this project aims at validating the hypotheses stated above and exploring the changes occurring in tumor cells with CICs and their effect on immune cells and their microenvironment. Utilizing gene editing methods to construct recombinant mammalian cells containing drug targets from lower organisms to explore the primitivity of mammalian cells and its potential biological value, it should be feasible to discover new ideas, phenomenon and strategies for deeper understanding of tumor growth, migration, drug-resistant and immune escape

Cell-in-cell(细胞叠套)是指一个或多个细胞进入另一个细胞并产生生物学效应的现象，普遍发生于低等到高等生物中，是古老和特殊的细胞相互作用模式。肿瘤微环境是体内细胞叠套最常见的区域，细胞叠套在其中扮演的角色日益受到关注。我们发现，在胁迫环境下，一些原本不形成细胞叠套结构的肿瘤细胞发生细胞叠套的能力激增，并可引发后续生理病理过程。推测这种能力是由哺乳动物细胞的祖性及其返祖行为造成的，可产生非预期的生物学效应。由此形成的细胞叠套结构中，肿瘤细胞可通过剥夺进入细胞的组分而获得新的生物学特征，并成为免疫微环境调变的启因。本课题旨在利用体外模拟肿瘤免疫微环境及其胁迫条件验证这一假设，并探讨肿瘤细胞变化及其对免疫细胞和微环境的影响；同时，利用基因编辑技术构建携带低等生物靶标的重组哺乳动物细胞返祖模型，验证哺乳动物细胞祖性特征及其潜在学术价值，为肿瘤生长、转移、耐药和免疫逃逸研究提供新思路和策略

Cell-in-cell(CIC，细胞叠套)是指一个或多个细胞进入另一个细胞并产生生物学效应的现象，普遍发生于低等到高等生物中，是古老和特殊的细胞相互作用模式。肿瘤微环境是体内细胞叠套最常见的区域，细胞叠套在其中扮演的角色日益受到关注。我们发现由肿瘤细胞内化免疫细胞形成的异质性CIC是肿瘤不良预后相关的独立预测因素，优于传统的组织学分级和TNM分期。还发现在细胞叠套过程中免疫细胞会向肿瘤细胞传递蛋白或mRNA等生物分子从而改变肿瘤细胞的生物学特征，从而证明细胞叠套是介导细胞间通讯中的新型途径，也是一种调变肿瘤免疫微环境的重要方式。此外还发现细胞因子IL-8和膜蛋白ARHGAP36能够分别通过P-cadherin/γ-catenin和P-cadherin/α-catenin增加细胞间粘附来促进同质cell-in-cell结构的形成，而膜脂成分胆固醇能够通过促进肌球蛋白的去磷酸化来抑制同质cell-in-cell结构的形成，并发现首个负性调控entotic cell-in-cell结构形成粘附蛋白家族分子——PCDH7，为靶向同质cell-in-cell结构形成治疗肿瘤提供了新的干预靶点。最后，本研究首次发现了一种全新的细胞有丝分裂监测（mitotic surveillance）机制，即，非整倍体子代细胞可以通过钻入相邻细胞，形成细胞叠套结构，通过激活p53信号通路，诱导了一种非凋亡性细胞死亡，套亡（entosis，细胞在另一个细胞内的溶酶体通路死亡）。被选择清除。再次证明细胞叠套所具备的生理意义。重要的是，这一发现也为免疫系统的定义提出了新的挑战，传统免疫学概念认为，执行免疫功能的细胞主要是由骨髓发育而来的细胞（淋巴细胞，单核细胞和粒细胞等），这一发现表明上皮细胞同样可以执行类免疫功能，实现自身稳定。