Protein Kinase Cz targets in Intestinal Cancer Stem Cells

描述（由申请人提供）：研究不同类型癌症的新证据揭示了一种相对罕见的所谓“癌症干细胞”（CSCs）群体，也称为“肿瘤启动细胞”（TICs），其与正常干细胞具有某些特征，包括干细胞样表型和功能。然而，人们对控制和调节tic功能的信号网络知之甚少，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。此外，即使在早期癌症中也发现了肿瘤内营养应激，并且与患者生存率低有关。因此，了解炎症和营养胁迫下控制癌症干细胞增殖的信号机制对于确定新的和更具选择性的癌症治疗靶点至关重要。在本研究中，我们将在体外和相关的体内小鼠癌症模型中研究调节tic生长特性的信号传导和代谢途径。促进tic存活的信号分子将是有希望的肿瘤抑制候选物。本项目将在PKC控制的一种新的信号通路框架下研究tic的代谢重编程。初步结果显示PKC？在营养胁迫条件下抑制人类结直肠癌细胞的生长，并在APC突变驱动的肠道癌变小鼠模型中发挥抑瘤作用。还有PKC的损失？导致体内肠道和类器官中干细胞活性的增加。此外,PKC吗?在包括结直肠肿瘤在内的几种人类癌症中缺失或低表达。这一点很重要，因为结直肠癌是最普遍的肿瘤之一，影响了很大一部分美国人口。因此，了解tic是如何受PKC调控的？这将有助于更好地理解肿瘤的发生和发现潜在的新治疗靶点。因此，我们将：(1)描述PKC的作用？PKC在肿瘤干细胞扩增中的作用？-控制肿瘤微环境中的炎症信号；(2)确定PKC的作用？在肿瘤干细胞增殖信号集中中调控癌细胞代谢。总之，我们将

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 PKC?. Our preliminary results show that PKC? 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 PKC? results in increased stem cell activity in the intestine in vivo and in organoids. Furthermore, PKC? 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 PKC? 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 PKC? in cancer stem cell expansion and the effect of PKC?-controlled inflammatory signals in the tumor microenvironment; and (2) Determine the role of PKC? in cancer stem cell proliferative signaling focusing in the control of cancer cell metabolism. In summary, here we will rigorously test the hypothesis that PKC? 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.