Molecular mechanisms of SCLC initiation and detection in mice and humans

小细胞肺癌(SCLC)是最致命的癌症之一，是一种顽固性癌症。 除非疾病被早期诊断，否则没有有效的治疗方法。然而，只有一小部分患者 是在疾病早期被诊断出来的。早期诊断的最大挑战是小细胞肺癌肿瘤细胞通常 获得异常的突变负担，并及早转移，因此对大多数患者来说，疾病已经传播 在诊断时在肺之外。发展有效的早期诊断和治疗的关键 方法是阐明肿瘤启动的最早分子和细胞事件，以揭示那些可以 在疾病的癌前阶段通过筛查被检测到。这项提案的目标是界定 小细胞肺癌的早期、癌前分子和细胞事件，以便及早发现和 在它们成为一种致命的、无法治愈的疾病之前被摧毁。 小细胞肺癌是一种神经内分泌癌。突出的起源细胞是肺神经内分泌(NE)细胞， 感知和反应肺部环境的神经感觉和神经分泌上皮细胞。 最近，一小部分NE细胞亚群被发现具有干细胞活性，增殖，分散，和 严重呼吸道损伤后对周围支气管上皮的补充。肿瘤抑制基因Rb的缺失 而p53在肿瘤抑制因子丧失后的几天内结构性地激活干细胞程序，即使在 没有受伤。在这个建议中，遗传学、细胞培养和单细胞基因组学的组合被用来 系统地在细胞分辨率下询问这些干细胞，无论是在健康的肺部还是在早期， 小细胞肺癌癌前阶段。目标是定义在Rb和Rb丢失后立即发生的分子事件 构成激活干细胞程序并启动其转化为癌症干细胞的P53 传播、突变和逃避免疫破坏，并识别它们分泌的信号可能允许 在肿瘤变得致命之前被检测出来。

Small cell lung carcinoma (SCLC) is one of the deadliest cancers, a “recalcitrant” cancer for which there is no effective treatment except when the disease is diagnosed early. However, only a small fraction of patients are diagnosed early in disease. The greatest challenge to early diagnosis is that SCLC tumor cells typically acquire an exceptional mutation burden and metastasize early, so for most patients disease has spread beyond the lung at the time of diagnosis. The key to developing effective early diagnosis and treatment methods is to elucidate the earliest molecular and cellular events of tumor initiation to uncover ones that can be detected by screening during the premalignant phase of the disease. The goal of this proposal is to define the early, premalignant molecular and cellular events of SCLC, so that they can be detected early and destroyed before they become a deadly, untreatable disease. SCLC is a neuroendocrine cancer. The prominent cell of origin is pulmonary neuroendocrine (NE) cells, neurosensory and neurosecretory epithelial cells that sense and respond to the environment in the lung. Recently, a minor subpopulation of NE cells was found to have stem cell activity, proliferating, dispersing, and replenishing the surrounding bronchial epithelium following severe airway injury. Loss of tumor suppressors Rb and p53 constitutively activates the stem cell program within days of loss of the tumor suppressors, even in the absence of injury. In this proposal, a combination of genetics, cell culture, and single-cell genomics is used to systematically interrogate these stem cells at cellular resolution, both in healthy lungs and in the early, premalignant stage of SCLC. The goal is to define the molecular events immediately following loss of Rb and p53 that constitutively activate the stem cell program and initiate their transformation into cancer stem cells that spread, mutate, and escape immune destruction, and to identify the signals they secrete that might allow the tumors to be detected before they become deadly.