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

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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.