Live analysis of tumor-host cells interactions

描述（由申请人提供）：组织稳态是一个高度动态的过程，需要严格调节组织内的细胞生长、细胞增殖和细胞死亡。在生物体的发育和成年期间，细胞增殖和细胞死亡精确地协调以确保上皮的完整性。然而，由于遗传改变，一些细胞可以将它们的增殖和死亡信号与上皮的其余部分解偶联，从而获得不受控制地增殖的自主能力。如果不纠正，这种细胞增殖和/或细胞死亡的失调又会导致组织内的肿瘤形成，潜在地导致组织/器官功能障碍和随后的个体/动物死亡。为了使肿瘤细胞有效地生长，它们必须克服几个挑战，包括其环境中的抗细胞增殖和/或促凋亡信号。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理解是不完整的。此外，原发性良性肿瘤中另外的信号传导途径的失调可以将这些肿瘤转化为恶性肿瘤，其具有扩散到远处器官并促使患者死亡的能力。癌症占人类恶性肿瘤的约90%，并且转移与患者预后不良相关。我们对这些恶性转化信号通路的性质以及这些信号如何在肿瘤细胞中内化以引起这种转化的理解尚不清楚。此外，现在很明显，肿瘤是功能异质性的。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。缺乏这些转移起始肿瘤细胞的表征。使用果蝇肿瘤模型，本研究计划的目的是1）研究良性肿瘤与恶性肿瘤中细胞增殖和细胞死亡信号的调节方式，2）测试TGF 2信号在良性肿瘤向恶性肿瘤转化中的作用，以及3）表征转移启动肿瘤细胞的细胞动力学特性。目标1.研究良性与恶性肿瘤细胞的细胞死亡和细胞增殖在果蝇肿瘤模型中使用实时成像技术，我将监测良性或恶性肿瘤中的肿瘤细胞增殖和细胞死亡。类似地，将同时分析邻近肿瘤细胞的野生型细胞的行为。目标2。为了研究TGF 2信号传导在良性至恶性肿瘤转化中的作用，将使用免疫染色和体细胞遗传方法检查TGF 2信号传导在将良性肿瘤转化为恶性肿瘤中的作用。目标3。描述转移起始肿瘤细胞的细胞动力学特性。将进行追踪实验以追踪转移性肿瘤细胞回到其在原发性肿瘤内相对于相邻野生型细胞的位置。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%，转移性肿瘤通常与患者预后不良相关。了解肿瘤如何与宿主细胞相互作用以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