Toll-like receptors in tissue-intrinsic defense against aberrant cells

组织固有的肿瘤抑制和防御机制，如细胞-细胞竞争，对维持组织和有机体的健康至关重要。然而，这些防御机制的失败会导致组织中异常细胞的持续存在，最终导致癌症的发生和肿瘤的形成。我们已经确定了一种新的组织内在防御机制，称为“界面监视”，它非常专门地防御经历了不适当的细胞命运和分化程序的细胞。这项提议旨在解决一个知之甚少的问题，即如何通过“界面监测”检测并消除上皮组织中的异常细胞。具体地说，我们将研究Toll样受体在细胞表面密码中作为分子参与者的作用，该密码使上皮细胞能够检测细胞命运差异，识别异常细胞，并激活杀伤机制来消除它们。为了实现我们的目标，我们将使用分子、细胞和发育生物学技术的标准组合，以及果蝇可用的优秀遗传工具。我们将首先建立一个全面的地图，在‘界面监测’的Toll样受体的功能，在想象的椎间盘上皮细胞。然后，我们将确定Toll样受体是否受细胞命运、致癌基因突变或组织内在防御过程的调控，如经典的细胞-细胞竞争。我们随后将揭示将相邻细胞表面之间的Toll样受体错配转化为“界面监视”标志的分子机制。我们将专门研究通过Toll诱导的NFkB驱动的转录反应而产生的信号的潜在下游影响，通常涉及炎症和先天免疫反应。因此，我们的工作将全面了解分子、细胞和组织水平上对异常细胞的内在防御机制，并深入了解“界面监视”和先天免疫之间的潜在协同效应。因此，我们将为组织固有的肿瘤抑制领域的新领域做出贡献，并揭示炎症、肿瘤起始和癌症进展的潜在临床意义。

Tissue-intrinsic tumor suppression and defense mechanisms, such as cell-cell competition, are crucial for maintaining tissue and organismal health. However, failure of these defense mechanisms can lead to the persistence of aberrant cells in tissues, ultimately resulting in cancer initiation and tumor formation. We have characterized a novel tissue-intrinsic defense mechanism called 'interface surveillance' that very specifically guards against cells which undergo inappropriate cell fate and differentiation programs. The proposal here aims to address the poorly understood question of how aberrant cells are detected and eliminated from epithelial tissues by 'interface surveillance'. Specifically, we will investigate the role of Toll-like receptors as molecular players in a cell surface code that enables epithelial cells to detect cell fate differences, identify abnormal cells and activate killing mechanisms to eliminate them. To achieve our goal, we will use a standard combination of molecular, cell, and developmental biology techniques, in conjunction with the excellent genetic tools available in Drosophila. We will first establish a comprehensive map of Toll-like receptor function during 'interface surveillance' in imaginal disc epithelia. We will then determine if Toll-like receptors are regulated by cell fate, oncogenic mutations, or tissue-intrinsic defense processes, such as classical cell-cell competition. We will subsequently uncover molecular mechanisms that transduce a Toll-like receptors mismatch between neighboring cell surfaces into 'interface surveillance' hallmarks. We will specifically examine potential downstream effects that result from signaling via Toll-induced NFkB-driven transcriptional responses, normally implicated in inflammatory and innate immune responses. Our work will thus provide a comprehensive understanding of molecular, cellular and tissue-level mechanisms underlying intrinsic defenses against aberrant cells, and insight into potential synergies between 'interface surveillance' and innate immunity. We will thereby contribute to new frontiers in the field of tissue-intrinsic tumor suppression and reveal potential clinical implications for inflammation, tumor initiation and cancer progression.