Live analysis of tumor-host cells interactions

描述(申请人提供)：组织动态平衡是一个高度动态的过程，它需要对组织内的细胞生长、细胞增殖和细胞死亡进行严格的调控。在生物体的发育和成体生命过程中，细胞增殖和细胞死亡是精确协调的，以确保上皮的完整性。然而，由于基因改变(S)，一些细胞可以将它们的增殖和死亡信号从其余的上皮细胞中分离出来，从而获得一种自主的无法控制的增殖能力。如果不加以纠正，这种对细胞增殖和/或细胞死亡的放松调控可能会反过来导致组织内肿瘤的形成，可能导致组织/器官功能障碍和随后的个人/动物死亡。为了让肿瘤细胞有效地生长，它们必须克服几个挑战，包括抗细胞增殖和/或环境中的促凋亡信号。然而，我们对肿瘤如何与宿主，特别是与邻近的野生型细胞相互作用的了解是不完整的。此外，在原发性良性肿瘤中，额外信号通路(S)的失控可以将这些肿瘤转变为恶性肿瘤，这些恶性肿瘤有能力扩散到远处的器官，并导致患者S死亡。癌症约占人类恶性肿瘤的90%，转移与患者预后不良有关。我们对这些恶性转化信号通路的性质以及这些信号如何内化到肿瘤细胞中导致这种转化的了解尚不清楚。此外，现在很明显，肿瘤在功能上是异质性的。例如，在任何给定的肿瘤中，细胞具有不同的启动肿瘤转移的潜力。目前尚缺乏对这些启动转移的肿瘤细胞的描述。利用果蝇肿瘤模型，本研究的目标是：1)研究细胞增殖和细胞死亡信号在良、恶性肿瘤中的调控；2)检测TGF2信号在良、恶性肿瘤转化中的作用；3)研究肿瘤转移始动细胞的细胞动力学特性。目的：1.为了在果蝇肿瘤模型中使用实时成像技术检测良、恶性肿瘤细胞的细胞死亡和细胞增殖，我将监测良、恶性肿瘤的肿瘤细胞增殖和细胞死亡。类似地，还将同时分析肿瘤细胞周围的野生型细胞的行为。AIM2.为了研究TGF2信号在良性肿瘤向恶性肿瘤转化中的作用，我们将利用免疫组织化学和体细胞遗传学方法来研究TGF2信号在良性肿瘤向恶性肿瘤转化中的作用。Aim3.目的：研究肿瘤转移始动细胞的细胞动力学特性。将进行追踪实验，将转移的肿瘤细胞追溯到它们在原发肿瘤中相对于邻近野生型细胞的位置。随后将分析它们的细胞增殖行为。 公共卫生相关性：癌症约占人类恶性肿瘤的90%，转移性肿瘤往往与患者预后不良有关。了解肿瘤如何与宿主细胞相互作用促进肿瘤生长和转移可能为临床干预提供新的见解

DESCRIPTION (provided by applicant): Tissue homeostasis is a highly dynamic process, which requires a strict regulation of cell growth, cell proliferation, and cell death within the tissue. During development and adult life of the organism, cell proliferation and cell death are precisely coordinated to ensure the integrity of the epithelium. However, due to genetic alteration(s) some cells can uncouple their proliferation and death cues from the rest of the epithelium and thus acquire an autonomous ability to proliferate uncontrollably. If not corrected, this deregulation of cell proliferation and/or cell death can in turn lead to tumor formation within the tissue, potentially causing tissue/organ malfunction and subsequent death of the individual/animal. For tumor cells to effectively grow they must overcome several challenges, including anti-cell proliferation and/or pro-apoptotic signals within their environment. However, our understanding of how tumors interact with the host, specifically with neighboring wild type cells is incomplete. Furthermore, deregulation of additional signaling pathway(s) in primary benign tumors can transform these tumors into malignant tumors, which have the ability to spread to distant organs and precipitate the patient<s death. Carcinomas account for ~90% of human malignancies and metastasis is associated with poor patients prognosis. Our understanding of the nature of these malignant transforming signaling pathways and how these cues are internalized in tumor cells to cause such transformation is unclear. Moreover, it is now evident that tumors are functionally heterogeneous. For example, in any given tumor, cells have differing potential to initiate tumor metastasis. A characterization of these metastasis-initiating tumor cells is lacking. Using a Drosophila tumor model, the objectives of this research proposal are 1) to investigate how cell proliferation and cell death cues are regulated in benign versus malignant tumors, 2) to test a role for TGF2 signaling in the benign to malignant tumor transformation, and 3) To characterize the cytokinetic properties of metastasis initiating tumor cells. Aim1. To examine cell death and cell proliferation of benign versus malignant tumor cells Using live imaging techniques in a Drosophila fly tumor model, I will monitor tumor cell proliferation and cell death in benign or malignant tumors. Similarly, the behavior of wild type cells neighboring tumor cells will be concomitantly analyzed. Aim2. To investigate a role for TGF2 signaling in the benign to malignant tumor transformation, A role for TGF2 signaling in converting benign tumors into malignant tumors will be examined using immuno- staining and somatic genetic approaches. Aim3. To characterize the cytokinetic properties of metastasis initiating tumor cells. Tracking experiments will be performed to trace metastatic tumor cells back to their position within the primary tumor relative to neighboring wild type cells. Their cell proliferation behaviors will subsequently be analyzed. PUBLIC HEALTH RELEVANCE: Carcinomas account for ~90% of human malignancies and metastatic tumors are often associated with poor patient prognosis. Understanding how tumors interact with host cells to facilitate tumor growth and metastasis could potentially provide novel insights for clinical interventions