Mechanisms and therapeutic targeting of colon cancer stem cell plasticity

结肠癌干细胞可塑性的机制和治疗靶点

• 批准号: 9896787
• 负责人: Kendra S. Carmon
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896787
• 关键词: ADGR1 gene; Ablation; Address; Adhesions; Affect; Affinity; Aftercare; Antibodies; Antibody-drug conjugates; Automobile Driving; Binding; Biological; Bispecific Antibodies; Cell Adhesion; Cell surface; Cell-Cell Adhesion; Cells; Cessation of life; Characteristics; Colon; Colon Carcinoma; Colonic Neoplasms; Data; Development; Disease; Drug resistance; EGF gene; Epiregulin; Epithelial; Epithelium; G-Protein-Coupled Receptors; Genetic; Goals; Growth; Growth Factor; IQ motif containing GTPase activating protein 1; Intestines; Knock-out; LGR5 gene; Label; Leucine-Rich Repeat; Ligands; Maintenance; Malignant Neoplasms; Mediating; Microarray Analysis; Modeling; Mucous Membrane; Natural regeneration; Neoplasm Metastasis; Normal tissue morphology; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Proliferating; Property; Protein Array Analysis; Recovery; Recurrent disease; Regulation; Relapse; Reporting; Research; Resistance; Rhodopsin; Role; STAT3 gene; Scaffolding Protein; Signal Pathway; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Tissues; Toxin; Tumor Tissue; Work; Xenograft Model; Xenograft procedure; adult stem cell; antibody conjugate; base; beta catenin; cancer cell; cancer drug resistance; cancer stem cell; cancer therapy; cell motility; chemotherapy; colon cancer cell line; colon cancer treatment; daughter cell; drug sensitivity; effective therapy; fitness; genome-wide; in vivo; innovation; insight; knock-down; member; novel; protein activation; receptor; safety testing; self-renewal; stem cell therapy; stem cells; stem-like cell; stemness; targeted treatment; theories; therapeutic target; therapy development; tool; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor xenograft; tumorigenesis

ABSTRACT: Tumor-initiating or cancer stem cells (CSCs) have been implicated in drug resistance, metastasis, and relapse, making CSCs a major impediment for the effective treatment of cancer. Recent studies have unequivocally established that the adult stem cell marker LGR5 (leucine-rich repeat-containing, G protein-coupled receptor 5) is highly expressed in primary colon tumors and only LGR5-positive colon CSCs are capable of driving tumor growth and metastasis. However, the function and mechanism of LGR5 in CSCs is still relatively unknown. We generated LGR5-targeted antibody-drug conjugates (ADCs) incorporating the toxin monomethyl-auristatin E and showed they could destroy colon cancer cells and xenografts, yet tumors eventually recurred. Furthermore, selective genetic ablation of LGR5-positive colon CSCs failed to completely eradicate tumors since LGR5-negative cancer cells were able to rapidly regenerate LGR5-positive cells after treatment was terminated, indicating a high degree of cancer cell plasticity. Therefore, to develop therapies that completely eradicate primary colon tumors and metastatic disease, it is critical to identify LGR5-mediated functions and signaling pathways involved in CSC plasticity. We reported that LGR5 binds R-spondin growth factors and functions to potentiate Wnt/beta-catenin signaling, an essential pathway that is activated in CSCs. Recently, we have found that LGR5 interacts with the scaffold protein IQGAP1 (IQ Motif Containing GTPase Activating Protein 1) to increase cell-cell adhesion in colon cancer cells and knockdown of LGR5 significantly enhanced drug resistance and activation of proteins associated with survival signaling. Loss of LGR5 induced expression of adhesion G-protein-coupled receptor GPR56, which is highly upregulated in colon tumors. In Aim 1, we will determine the roles and mechanisms of LGR5 in the control of stemness and drug resistance of CSCs. We will investigate how LGR5 knockout (KO) compared to elimination of LGR5-positive CSCs affects tumor growth, metastasis, drug resistance, and cancer cell signaling using patient-derived xenograft (PDX) organoids models ex vivo and in vivo. The role of LGR5-IQGAP1 interaction in regulating the different properties that define CSCs will also be examined. In Aim 2, we will develop unique bispecific ADCs to target CSC plasticity. We will test safety, efficacy and establish proof-of-concept for dual-targeted therapeutics to simultaneously destroy both LGR5-positive CSCs and LGR5-negative cancer cells. In Aim 3, we will characterize and validate GPR56 as a novel target for colon cancer by delineating its roles in tumor growth and drug resistance using GPR56 KO colon cancer cell lines and PDX models. This study will uncover the function and mechanism of LGR5 in CSCs and generate innovative therapeutic leads to target stemness and plasticity for the treatment and eradication of colon cancer.

文摘: