成体干细胞能在动物一生中不断地进行自我更新及分化产生终末分化的细胞来补充和修复组织。因而成体干细胞对机体的组织稳态和损伤修复发挥着至关重要的作用。干细胞在体内必须受到精细的调控以确保其自我更新和分化之间的平衡，这种平衡关系一旦打破将引起严重的疾病如肿瘤、组织衰退和早衰。用果蝇作为模式生物研究干细胞生物学已经有很长的时间，果蝇生殖干细胞的研究更是取得了丰硕的成果。近年来，果蝇消化道被发现存在多种干细胞，由于果蝇肠道与脊椎动物肠道在功能和细胞组成方面的相似性，果蝇消化道也已经成为一个非常有吸引力的研究干细胞的系统。 APC和Ras是结直肠癌患者中最常见的发生突变的两个基因。经典的结直肠癌发生模型认为APC突变导致了Wnt信号通路的过度激活从而引发腺瘤的起始，而腺瘤往结直肠癌发展还需要累积一系列其他转化性的突变，比如Ras等。然而近年来的关于Ras在APC突变所致肿瘤发生中的作用机制的研究得出了一些与此抵触的观点。我们利用果蝇中肠作为模式，探究了Ras对APC突变引起的肿瘤形成的作用。我们发现缺失Ras时，APC突变不能形成肠道肿瘤，表明Ras对APC突变引发的肿瘤发生是必需的。相反，如果在APC突变的同时激活Ras或Raf会肿瘤表现出晚期结直肠癌中的一些特点：细胞极性受到损害，分化受到抑制并表现出向附近组织侵袭生长的倾向。在机制上，我们发现Ras对APC突变所致Wnt信号通路的激活不是必需的但是激活Ras能促进Armadillo/β-catenin在APC突变细胞的细胞质和细胞核中积累从而增强Wnt信号通路。Ras激活导致 Armadillo/β-catenin的定位改变不是通过JNK/Rac1和PI3K/Akt，而是部分地通过降低E-cadherin的表达水平。此外，基因表达谱分析揭示Ras和Wnt信号通路调控的下游靶基因重叠很少。综上，我们的结果表明在果蝇中Ras和Wnt信号通路平行且协同地促进APC突变导致的肠道肿瘤产生和发展。 果蝇的胃干细胞是分裂缓慢的多能干细胞，能分化形成胃铜细胞区域上皮的三类细胞:泌酸的铜细胞、间质细胞和肠分泌细胞。但是果蝇胃干细胞的分化机制尚不清楚。我们研究了Dl-Notch信号通路对胃干细胞的分化的作用。通过细胞消除或化学物质损伤导致的修复并结合细胞谱系追踪的方法，我们确定了表达Dl的细胞是真正的胃干细胞，介导了损伤后的胃上皮修复。并且发现在抑制Notch信号通路情况下胃干细胞不能分化形成铜细胞和间质细胞而导致胃干细胞样的肿瘤及肠内分泌细胞样的肿瘤形成，相反如果激活Notch则促使胃干细胞往铜细胞和间质细胞分化。综上，我们发现确定了Dl是GSSC特异的标记分子，并且Dl-Notch信号通路对GSSC朝铜细胞和间质细胞分化起充分且必要的作用

Adult stem cells are vital to tissue homeostasis and regeneration, because of their life-long abilities to self-renew and differentiate into specialized cell types for tissue replenishment and repair. The counterbalance between self-renewal and differentiation must be precisely regulated, as dysfunction of adult stem cells may lead to tumorigenesis, tissue degeneration and precocious aging. Studying stem cells in Drosophila, such as germline stem cells, has provided important insights into adult stem cell biology, and recent identification of several types of adult stem cell populations along the Drosophila digestive tract has made Drosophila as a powerful genetic model for the understanding of intestinal stem cell regulation, intestinal homeostasis and diseases.Adenomatous polyposis coli (APC) and K-ras are the two most frequently mutated genes found in human colorectal cancers. In human colorectal cancers, Wnt signaling activation after the loss of APC is hypothesized to be the key event for adenoma initiation, whereas additional mutations such as Ras activation are required for the progression from adenoma to carcinoma. However, accumulating data have led to conflicting views regarding the precise role of Ras in APC loss-induced tumorigenesis. Here, using Drosophila midgut as a model system, we show that in the absence of Ras, APC mutant epithelial cells cannot initiate hyperplasia, suggesting that Ras plays an essential role in tumor initiation. Conversely, activating Ras by expressing oncogenic Ras or Raf in APC-deficient cells affected cell polarity and cell differentiation and led to preinvasive tumor outgrowth, characteristics that are shared by advanced colorectal carcinoma in humans. Mechanistically, we found that Ras is not required for Wnt signaling activation after APC loss, although Ras hyperactivation is able to potentiate Wnt signaling by increasing the cytoplasmic and nuclear accumulation of Armadillo/β-catenin via mechanisms independent of JNK/Rac1 or PI3K-Akt signaling, partly owing to the downregulation of DE-cadherin. Together with the data from gene expression analyses, our results indicate that both parallel and cooperative mechanisms of Wnt and Ras signaling are responsible for the initiation and progression of intestinal tumorigenesis after APC loss.Quiescent, multipotent gastric stem cells (GSSCs) in the copper cell region of adult Drosophila midgut can produce all epithelial cell lineages found in the region, including acid-secreting copper cells, interstitial cells and enteroendocrine cells, but mechanisms controlling this ternary lineage differentiation are unknown. By using cell-ablation or damage-induced regeneration assays combined with cell lineage tracing and genetic analysis, here we demonstrate that Delta (Dl)-expressing cells in the copper cell region are the authentic GSSCs that are long-term maintained and are responsible for the regeneration of the entire gastric epithelium following damage. Loss-of-functional and gain-of-functional analysis revealed that Notch signaling is both necessary and sufficient for copper cell/ interstitial cell differentiation. Our results demonstrate that that Dl is a specific marker for Drosophila GSSCs, and Notch signaling has a central role in separating copper/interstitial cell lineage from enteroendocrine cell lineage during GSSC differentiation.