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Dissecting the intrinsic and extrinsic regulators of prostate cancer dormancy in the bonemicroenvironment.

剖析骨微环境中前列腺癌休眠的内在和外在调节因子。

基本信息

批准号：
10743406
负责人：
Mostafa Nasr
金额：
$ 4.12万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-11 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10743406
关键词：
ACVR1 gene Ablation Address Aging Agreement American Androgens Apoptosis Apoptotic Arteries BCL-2 Protein BCL1 Oncogene BCL2L11 gene BMP7 gene Benign Bioinformatics Biological Bioluminescence CASP3 gene CDK4 gene Cancer Etiology Cancer Patient Castration Cell Communication Cell Cycle Progression Cell Cycle Regulation Cell Line Cells Cessation of life ChIP-seq Coculture Techniques Cytometry DNA Binding Data Diagnosis Disease model Ectopic Expression Fluorescence-Activated Cell Sorting Gene Expression Profiling Genes Genetic Growth Hemostatic Agents Histologic Homeostasis Human Immunocompetent Impairment In Vitro Knowledge LAPC4 Lesion Limb structure Literature Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Methods Modeling Molecular Molecular Target Mus Neoplasm Metastasis Operative Surgical Procedures Parents Pathway Analysis Pathway interactions Patients Phase Phosphorylation Pre-Clinical Model Primary Neoplasm Protein Region Proteins Publishing Recurrent disease Relapse Research Research Proposals Resistance Role Sampling Signal Transduction Site Skeleton Small Interfering RNA Stromal Cells Survival Rate Techniques Technology Testing Tissues Up-Regulation Validation Work Xenograft Model Zinc Fingers antagonist bone cancer cell experimental study genetic approach high dimensionality improved in vitro Model in vivo in vivo evaluation inhibitor insight knock-down men mortality mutant neoplastic cell novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase patient prognosis pharmacologic prevent pro-apoptotic protein programs prostate cancer cell prostate cancer cell line prostate cancer model receptor receptor expression single-cell RNA sequencing skeletal stem cells transcription factor transcriptome transcriptome sequencing treatment strategy tumor

项目摘要

Project Summary / Abstract………………………………………………………………………………..…. Metastatic prostate cancer (PC) typically manifests in the skeleton. The lesions arise from disseminated tumor cells (DTCs) that often persist in a dormant state for months to decades after initial primary tumor treatment. Despite our knowledge that DTCs give rise to incurable bone metastatic PC, there remains gaps in our understanding as to the molecular mechanisms underpinning entry and reawakening from the dormancy program. Insight into those mechanisms could yield new therapeutic approaches that would prevent the metastatic relapse and ultimately death of almost 34,500 American men each year. To address this, we have developed a novel model of PC dormancy in agreement with published markers in the literature in vitro and optimized a surgical technique to study dormancy in vivo. We next performed transcriptomic sequencing on PC cells growing under normal, dormant, or reawakening conditions. Bioinformatic analysis of transcript expression and transcription factor (TF) activity revealed positive regulatory domain zinc finger region protein 16 (PRDM16) to significantly increase during entry into dormancy and decrease during exit across mouse (RM1) and human sensitive / castrate resistance cell lines (LAPC4, 22Rv1). Further, we validated PRDM16 upregulation in dormant cells on the protein level both in vitro and in vivo. Genetic silencing of PRDM16 led to a significant reduction in the ability of PC cells to enter dormancy concomitant with decreased expression of anti-apoptotic proteins including BCL-2 and increased pro-apoptotic proteins such as BIM & Noxa. Preliminary data shows that PRDM16 expression in PC cells can be induced by BMP-7 and conversely decreased by the BMP signaling antagonist, noggin, factors with known critical roles in regulating bone homeostasis. Based on our findings, we hypothesize that BMP7 induces PRDM16 expression in early skeletal DTCs, which is critical for the initiation of the dormancy program. In the F99 phase, we will identify PRDM16 transcriptome in PC dormancy and confirm BMP signaling control on its expression using genetic approaches and validation of findings in pre-clinical models. In K00 phase, we will study how aging contribute to the reawakening of dormant cancer cells in the bone microenvironment. We will identify biological and molecular determinants of cancer dormancy using Cherry-niche technology and comprehensive fluorescence-activated cell sorting (FACS), high dimensional mass cytometry, and single cell RNASeq experiments. We will then validate our findings in pre-clinical models and patient tissue sections. Findings from this work will advance our understanding of the intrinsic and extrinsic factors regulating the cancer dormancy program in skeletal metastasis in the context of aging, which is relevant to most prostate cancer patients.

项目概要/摘要...... 转移性前列腺癌（PC）通常表现在骨骼中。病变起源于播散性肿瘤细胞（DTC）通常在最初的原发性肿瘤后持续数月至数十年的休眠状态治疗尽管我们知道DTC会引起不可治愈的骨转移性PC，但仍然存在我们对进入和重新觉醒的分子机制的理解存在差距，休眠程序深入了解这些机制可以产生新的治疗方法，每年将防止近34，500名美国男性的转移复发和最终死亡。为了解决这个问题，我们已经开发了一种新的PC休眠模型，标记物在体外文献中，并优化了手术技术，研究休眠在体内。我们接下来对在正常、休眠或重新唤醒状态下生长的PC细胞进行转录组测序条件转录本表达和转录因子（TF）活性的生物信息学分析显示，正调控域锌指区蛋白16（PRDM 16）在进入过程中显著增加进入休眠，并在小鼠（RM 1）和人类敏感/去势抵抗退出期间减少细胞系（LAPC 4，22 Rv 1）。此外，我们验证了PRDM 16在休眠细胞中对蛋白质表达的上调。在体外和体内的水平。PRDM 16的基因沉默导致了细胞的表达能力的显著降低。 PC细胞进入休眠伴随着抗凋亡蛋白的表达减少包括BCL-2和增加的促凋亡蛋白如BIM和Noxa。初步数据显示 PC细胞中PRDM 16的表达可被BMP-7诱导，相反地被BMP-7降低。信号传导拮抗剂，头蛋白，已知在调节骨稳态中具有关键作用的因子。基于根据我们的发现，我们假设BMP 7在早期骨骼DTC中诱导PRDM 16表达，这对于休眠程序的启动至关重要。在F99阶段，我们将鉴定PC休眠中的PRDM 16转录组，并确认BMP 使用遗传方法对其表达进行信号控制，并验证临床前研究结果模型在K 00阶段，我们将研究衰老如何有助于休眠癌细胞的重新唤醒在骨骼微环境中。我们将确定癌症的生物和分子决定因素利用Cherry-niche技术和综合荧光激活细胞分选休眠流式细胞术（FACS）、高维质谱细胞术和单细胞RNASeq实验。然后我们将验证我们在临床前模型和患者组织切片中的发现。这项工作的结果将推动我们的了解骨骼肌中调节癌症休眠程序的内在和外在因素，前列腺癌患者的前列腺癌转移与年龄有关。