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揭示了相对罕见的所谓“癌症干细胞”（CSC）群体，也称为“肿瘤起始细胞”（TICs），它们与正常干细胞具有某些共同特征，包括干细胞样表型和功能。然而，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相关。因此，了解炎症和营养应激下控制癌症干细胞增殖的信号传导机制对于识别癌症中新的和更具选择性的治疗靶点至关重要。 在这个提议中，我们将研究信号和代谢途径，调节TIC在体外和相关的体内小鼠癌症模型的生长特性。促进TIC存活的信号分子将是有希望的肿瘤抑制剂候选者。本项目将在PKC β调控的新型信号通路框架下研究TIC的代谢重编程。我们的初步研究结果表明，PKC β在营养应激条件下抑制人结直肠癌细胞的细胞生长，并且在APC突变驱动的小鼠肠道癌变模型中起肿瘤抑制作用。此外，PKC β的损失导致体内肠和类器官中干细胞活性增加。此外，PKC β在几种类型的人类癌症中不存在或表达不足，包括结肠直肠肿瘤。这一点很重要，因为结直肠癌是最常见的肿瘤之一，影响了大部分美国人口。因此，了解TICs是如何被PKC β调节的，对于更好地理解肿瘤的发生和识别潜在的新的治疗靶点具有重要意义。因此，我们将：（1）研究PKC β在肿瘤干细胞扩增中的作用，以及PKC β在肿瘤干细胞增殖中的作用。 肿瘤微环境中PKC β控制的炎症信号;和（2）确定PKC β在癌症干细胞增殖信号传导中的作用，集中在控制癌细胞代谢。总之，在这里，我们将严格测试的假设，在肠道干细胞中的PKC β消融将占起始因子增加TIC的数量和增殖活性。因此，更好地理解调节癌症干细胞信号传导的信号级联将产生重大影响，因为它将有助于设计新的更有效和更有选择性的治疗方法。

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.