Androgen Signaling in CaP with loss of MAP3K7 and CHD1

MAP3K7 和 CHD1 缺失的 CaP 中的雄激素信号转导

• 批准号: 10276486
• 负责人: Scott D Cramer
• 金额: $ 39.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10276486
• 关键词: Androgens; Animal Model; Binding; Biochemical; CHD1 gene; CWR22Rv1; Cell model; Cells; ChIP-seq; Clinical; Clinical Data; Collaborations; Complex; DNA Sequence Rearrangement; Data; Development; Disease; Disease-Free Survival; E-Cadherin; Eph Family Receptors; Ephrins; Future; Gene Expression; Genes; Genomics; Global Change; Growth; Human Cell Line; In Vitro; KLK3 gene; LAPC4; LNCaP; Lead; Length; MAP3K7 gene; Malignant neoplasm of prostate; Mediating; Messenger RNA; Metastatic malignant neoplasm to brain; Modeling; Mus; Mutation; Neurons; Neurosecretory Systems; Nuclear Atypia; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Primary Neoplasm; Prognosis; Prostate; Protein Isoforms; Proteins; RNA Splicing; Receptor Protein-Tyrosine Kinases; Recurrence; Regulation; Relapse; Resistance; Risk; Role; Sampling; Signal Transduction; Spliceosomes; Testing; The Cancer Genome Atlas; Therapeutic; Transforming Growth Factor beta; Translating; Up-Regulation; Variant; Work; advanced prostate cancer; base; cancer cell; castration resistant prostate cancer; cell motility; cohort; functional genomics; genomic data; in vivo; innovation; knock-down; mRNA Expression; men; new therapeutic target; novel; prostate cancer model; prostate carcinogenesis; protein expression; stem cells; success; transcriptome sequencing; tumor

Prostate cancer is characterized by large genomic rearrangements and deletions. We show that the genes CHD1 and MAP3K7 are co-deleted in ERG translocation negative prostate cancer. To demonstrate a functional cooperativity we used a novel mouse prostate stem cell developmental model and showed that collaborative loss of CHD1 and MAP3K7 promotes an aggressive prostate cancer phenotype with altered lineage differentiation, abnormal secretory products, massive nuclear atypia, loss of E-cadherin and enrichment in neuronal and neuroendocrine markers. Profound alterations in AR expression were also observed. Using multiple human cell line models we also demonstrate that loss of CHD1 and MAP3K7 promotes castrate-resistant prostate cancer. This project will evaluate downstream targets of AR altered in tumors with loss of MAP3K7 and CHD1 using functional genomics in vitro and in animal models and assess the clinical impact of these targets on patient outcome. This work could have impact on the management of the most aggressive prostate cancer. Co-deletion of CHD1 and MAP3K7 occurs in 10-15 % of primary tumors. Relapse occurs in approximately 50% of patients with co-deletion. If these deletions occur in primary tumors and predict poor survival, men could be stratified based on MAP3K7 and CHD1 status. A functional understanding of this variant of prostate cancer could lead to novel therapeutic targeting strategies in the future.

前列腺癌的特点是大量的基因组重排和缺失。我们证明基因 ERG 易位阴性前列腺癌中 CHD1 和 MAP3K7 共同缺失。为了演示一个 功能协同性我们使用了一种新型的小鼠前列腺干细胞发育模型并表明 CHD1 和 MAP3K7 的协同缺失会促进侵袭性前列腺癌表型的改变 谱系分化、异常分泌产物、大量核异型性、E-钙粘蛋白和 神经元和神经内分泌标记物的富集。 AR表达也发生了深刻的改变 观察到。使用多个人类细胞系模型，我们还证明了 CHD1 和 MAP3K7 的缺失 促进去势抵抗性前列腺癌。该项目将评估 AR 下游目标的改变 使用功能基因组学在体外和动物模型中检测 MAP3K7 和 CHD1 缺失的肿瘤并进行评估 这些目标对患者结果的临床影响。这项工作可能会对管理产生影响 最具侵袭性的前列腺癌。 CHD1 和 MAP3K7 的共同缺失发生在 10-15% 的原发性肿瘤中。 大约 50% 的共缺失患者会出现复发。如果这些缺失发生在原发性肿瘤中 并预测较差的生存率，可以根据 MA​​P3K7 和 CHD1 状态对男性进行分层。功能性的 对前列腺癌这种变异的了解可能会在未来带来新的治疗靶向策略。