Identification and characterization of novel gene networks connecting cancer and aging

成体干细胞在衰老过程中会受到环境压力和细胞内损伤。长寿似乎与干细胞更新能力的增强有关，但也与癌症风险的增加有关。相反，衰老与干细胞数量或功能的紊乱有关。这种长寿（衰老）和癌症之间的权衡被一些发现进一步加强，这些发现表明，几种实体癌症类型中含有可能来源于正常干细胞或祖细胞的癌症干细胞。肿瘤干细胞可能导致治疗抵抗和肿瘤复发。这一研究提议源于在果蝇高通量无偏表达获得基因筛选中鉴定出两个与衰老相关的基因Indy和kr<s:1> ppel同源基因1 （kr-h1）是恶性生长的促进因子。我注意到携带kr-h1诱导肿瘤的果蝇在羽化后24小时死亡，其缺陷与衰老的果蝇相似。提出的工作旨在利用成熟的果蝇遗传学，分子生物学和生物化学来确定这些观察结果背后的机制。特别是，我打算利用定量质谱分析的优势，并建议通过基因组和蛋白质组范围的分析，鉴定在干细胞区室中幼龄和老年果蝇中具有不同功能或表达的Indy和/或kr-h1基因网络。定量质谱分析的结果将在果蝇肿瘤范例和人类癌细胞中进一步研究。这些研究将有助于确定目前分开的衰老和癌症研究领域的共同网络。

Adult stem cells are exposed to environmental stress and intracellular damages that go together with the process of aging. Longevity seems to be associated with increased renewal capacity via stem cells but also with increased cancer risk. In contrast, aging is associated with disturbance in stem cell number or function. This trade-off between longevity (aging) and cancer is further strengthened by findings that several solid cancer types harbor cancer stem cells that may derive from normal stem- or progenitor cells. Cancer stem cells are likely to contribute to therapy resistance and tumor relapse. This fellowship proposal stems from the identification of two aging-related genes Indy and krüppel homolog 1 (kr-h1) as enhancers of malignant growth in a high throughput unbiased gain-of-expression genetic screen in Drosophila. I noted that flies bearing kr-h1-induced tumors die 24 hours after eclosion with defects reminiscent to aged flies. The proposed work aims to identify the mechanism behind these observations using well-established Drosophila genetics, molecular biology and biochemistry. Particularly, I intend to take advantage of quantitative mass spectrometry and propose to identify, through genome and proteome-wide analyses, Indy and/or kr-h1 gene networks that have differential function or expression in young and aged flies in stem cell compartments. Results from quantitative mass spectrometry will be further investigated in a Drosophila tumor paradigm and in human cancer cells. These studies will help to identify common networks of the currently separated research fields of aging and cancer.