Protein Kinase Cz targets in Intestinal Cancer Stem Cells

肠癌干细胞中的蛋白激酶 Cz 靶点

• 批准号: 9054084
• 负责人: Jorge Moscat
• 金额: $ 44.55万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054084
• 关键词: Ablation; Accounting; Affect; Biological Models; Bone Marrow; Cancer Model; Cell Proliferation; Cells; Cellular Metabolic Process; Characteristics; Chimera organism; Colon Carcinoma; Colorectal Cancer; Colorectal Neoplasms; Data; Diagnostic Neoplasm Staging; Future; Glucose; Glutamine; Goals; Growth; Health; Human; In Vitro; Inflammation; Inflammatory; Intestinal Cancer; Intestines; Knockout Mice; Label; Large Intestine Carcinoma; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mus; Mutagens; Mutation; Neoplasms; Nutrient; Organoids; Patients; Peptide Initiation Factors; Phenotype; Physiology; Play; Population; Process; Proliferating; Property; Protein Kinase; Regulation; Relapse; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stem cells; Stress; System; Testing; Therapeutic; Tumor Expansion; Tumor Suppressor Proteins; adenoma; base; cancer cell; cancer initiation; cancer stem cell; cancer therapy; cancer type; carcinogenesis; cell growth; chemotherapy; design; in vivo; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; potential biomarker; programs; response; self-renewal; stem cell population; therapeutic target; therapy resistant; tumor; tumor initiation; tumor metabolism; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

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.

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”（CSC）群体，也称为“肿瘤起始细胞”（TIC），它们具有某些共同特征然而，对于控制和调节 TIC 功能的信号网络，特别是那些影响正常或炎症细胞生长特性的信号网络，人们知之甚少。此外，即使在早期癌症中也发现了肿瘤内营养应激，并且与患者生存不良相关，因此，了解炎症和营养应激下控制癌症干细胞增殖的信号机制对于识别新的肿瘤干细胞至关重要。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 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前途的肿瘤。该项目的抑制器候选人。我们将在 PKC z 控制的新型信号通路框架内研究 TIC 的代谢重编程。我们的初步结果表明，PKC z 在营养应激条件下抑制人结直肠癌细胞的细胞生长，并在小鼠模型中发挥肿瘤抑制作用。 APC 突变驱动的肠道癌发生的过程中，PKC z 的缺失也会导致体内肠道和类器官中干细胞活性的增加。此外，PKC z 不存在，或在多种类型的人类癌症中，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，影响着很大一部分美国人口，因此，了解 TIC 如何受 PKC 调节将具有重要意义。因此，我们将：（1）表征 PKC z 在癌症干细胞扩增中的作用以及其作用。 肿瘤微环境中 PKC z 控制的炎症信号；以及（2）确定 PKC z 在癌症干细胞增殖信号中的作用，重点是控制癌细胞代谢。 总之，这里我们将严格检验 PKC z 在肠道中消融的假设。干细胞将解释增加 TIC 数量和增殖活性的启动因素，因此，更好地了解调节癌症干细胞信号传导的信号级联将产生巨大影响，因为它将有助于。设计新的更有效和选择性的疗法。