Protein Kinase Cz targets in Intestinal Cancer Stem Cells

描述(申请人提供)：研究不同类型癌症的新证据显示，有一种相对罕见的所谓“癌症干细胞”(CSCs)，也称为“肿瘤起始细胞”(TICs)，它们与正常干细胞有某些特征，包括干细胞样的表型和功能。然而，对于控制和调节抽动的功能的信号网络，特别是那些在正常或炎症微环境中影响其细胞生长特性的信号网络，人们知之甚少。此外，甚至在早期癌症中也发现了肿瘤内的营养应激，并与患者较差的存活率有关。因此，了解炎症和营养应激条件下调控肿瘤干细胞增殖的信号机制，对于寻找新的、更具选择性的肿瘤治疗靶点具有重要意义。在这项提案中，我们将研究在体外和相关的体内小鼠癌症模型中调节TICS生长特性的信号和代谢途径。促进痉挛存活的信号分子将是很有希望的肿瘤抑制候选药物。本项目将在一个新的信号通路的框架内研究TICS的代谢重编程，该信号通路由PKCζ控制。我们的初步结果表明，在营养应激条件下，PKCζ抑制了人结直肠癌细胞的生长，并在由APC突变驱动的小鼠肠道癌变模型中发挥了肿瘤抑制作用。此外，PKCζ的缺失也会导致体内肠道和器官中干细胞活性的增加。此外，PKCζ在几种类型的人类癌症中缺失或表达不足，包括结直肠肿瘤。这一点意义重大，因为结直肠癌是最常见的肿瘤之一，影响到美国人口的很大一部分。因此，了解抽动是如何被PKCζ调控的，对于更好地理解肿瘤的启动和识别潜在的新的治疗靶点将是相关的。因此，我们将：(1)研究pkcζ在肿瘤干细胞扩增中的作用以及pkc rle在肿瘤干细胞增殖中的作用。 PKCζ控制肿瘤微环境中的炎症信号；以及(2)确定PKCζ在肿瘤干细胞增殖信号中的作用，集中在控制癌细胞代谢方面。综上所述，我们将严格检验这一假设，即在肠道干细胞中去除PKCζ将解释增加抽动的数量和增殖活性的启动因素。因此，更好地了解调控癌症干细胞信号的信号级联将具有重大影响，因为这将有助于设计更有效和更有选择性的新疗法。

DESCRIPTION (provided by applicant): Emerging evidences studying different types of cancer have revealed a relatively rare population of so called ''cancer stem cells'' (CSCs), also known as "tumor-initiating cells" (TICs), which share certain characteristics with normal stem cells, including a stem cell-like phenotype and function. However, little is known about the signaling networks that control and regulate the function of the TICs, particularly those that influence their cell growth properties in a normal or an inflammatory microenvironment. Also, intratumoral nutrient stress has been found even in early-stage cancers, and is correlated with poor patient survival. Therefore, understanding the signaling mechanisms governing cancer stem cell proliferation under inflammation and nutrient stress is of paramount importance for the identification of new and more selective therapeutic targets in cancer. In this proposal we will investigate the signaling and metabolic pathways that regulate the growth properties of TICs in vitro and in a relevant in vivo mouse cancer model. Signaling molecules that promote the survival of TICs will be promising tumor suppressor candidates. This project will investigate the metabolism reprogramming of TICs in the framework of a novel signaling pathway controlled by PKCζ. Our preliminary results show that PKCζ represses cell growth of human colorectal cancer cells under nutrient stress conditions, and that it plays a tumor suppressive role in a mouse model of intestinal carcinogenesis driven by APC mutation. Also the loss o of PKCζ results in increased stem cell activity in the intestine in vivo and in organoids. Furthermore, PKCζ is absent, or underexpressed, in several types of human cancers, including colorectal neoplasias. This is significant because colorectal cancer is one of the most prevalent neoplasias, affecting a large portion of the US population. Therefore, understanding how TICs are regulated by PKCζ will be of relevant for a better understanding of tumor initiation and the identification of potentially novel therapeutic targets. Therefore, we will: (1) Characterize the rle of PKCζ in cancer stem cell expansion and the effect of PKCζ-controlled inflammatory signals in the tumor microenvironment; and (2) Determine the role of PKCζ in cancer stem cell proliferative signaling focusing in the control of cancer cell metabolism. In summary, here we will rigorously test the hypothesis that PKCζ ablation in the intestinal stem cells would account for the initiation factors increasing the number and proliferative activity of TICs. Therefore, a bette understanding of the signaling cascades that regulate cancer stem cell signaling would be of great impact as it will aid in the design of new more efficacious and selective therapies.