ARF GTPase regulation of prostate tumorigenesis: spheroid and in vivo approaches

ARF GTPase 对前列腺肿瘤发生的调节：球体和体内方法

• 批准号: 8542606
• 负责人: David Michael Bryant
• 金额: $ 16.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-08 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542606
• 关键词: ADP-Ribosylation Factors; Acinus organ component; Affect; Anatomy; Androgens; Apical; Architecture; Automobile Driving; Award; Back; Benign; Biopsy; California; Carcinoma; Castration; Cause of Death; Cell Line; Cell Polarity; Cell physiology; Cells; Characteristics; Clinical Data; Communication; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Epithelial; Epithelial Cells; Family; Feeds; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Human; Human Biology; In Vitro; Interleukin-6; Intervention; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Microscopy; Molecular; Molecular Target; Morphogenesis; Normal tissue morphology; Oncogenic; Paris, France; Pathway interactions; Patients; Phase; Property; Prostate; Prostatic Diseases; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Proteins; Recurrence; Regulation; Research; Research Personnel; Resistance; Role; San Francisco; Signal Pathway; Signal Transduction; Staging; Techniques; Therapeutic Intervention; Tissue Sample; Tissues; Training; Transmembrane Transport; Universities; Work; Writing; cancer gene expression; cancer genetics; cancer genomics; career; castration resistant prostate cancer; cell behavior; genetic regulatory protein; in vivo; member; men; mouse model; novel; overexpression; prostate carcinogenesis; protein expression; skills; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Cells of many tissues are polarized, collectively forming configurations tailored to the needs of a tissue. A common feature of most cancers of epithelial origin is the loss of normal tissue architecture. Despite advances in identifying signaling pathways involved in driving cancer progression, little is known about how polarity is disrupted during transformation. Dr. David Bryant studies the molecular control of epithelial polarity. His long- term goal as an independent biomedical researcher is to understand how epithelial polarity goes awry during tumor formation. With this award, Dr. Bryant will examine the ADP-ribosylation factor (ARF) GTPase family and their regulatory molecules (the ARF 'regulome') in control of polarity during prostate cancer, as 'regulome' members are highly overexpressed in human prostate cancers. This K99/R00 award will allow Dr. Bryant to achieve the following career goals: 1) additional training in prostate biology, and human cancer genetics, 2) develop genomic skills for analyses of human prostate cancer gene expression, 3) gain skills in immunohistochemical and histopathological techniques to analyze tissue samples of human biopsies and mouse models of prostate cancer from in vivo, and 4) develop the communication, mentoring, grant-writing, and laboratory management skills necessary to become and successful, independent biomedical researcher. The mentored phase of this research will be carried out at the University of California, San Francisco under the guidance of Dr. Keith Mostov. During the mentored phase, Dr. Bryant will use the combined approaches of genetics, semi-automated microscopy, and in vitro spheroid culture of normal and tumorigenic prostate epithelial cells to define changes in ARF regulome expression that control prostate acinar morphogenesis (Aim 1). Next, he will elucidate the interplay between the ARF regulome and oncogenic pathways leading to castration-resistant prostate cancer (Aim 2). To identify potential disease stage-specific ARF regulome alterations during prostate cancer progression in vivo (Aim 3), Dr. Bryant will begin using genomic and immunohistochemical analysis of tumors from human patients and mouse models of prostate cancer of varying disease stage. Drs. Pamela Paris, Davide Ruggero (UCSF), experts in prostate cancer genomics and cancer genetics, respectively, will serve as collaborators and advisors. During the independent phase, Dr. Bryant will continue to focus on Aims 2 and 3, the mechanisms of ARF regulome-controlled epithelial polarity, and in vivo analysis of ARF regulome alterations in tumors. This award will enable Dr Bryant to examine the molecular regulation of prostate epithelial polarity in a rapid, medium-throughput fashion, enabling development of selective interventions that inhibit the ARF regulome pathway, and potentially identifying novel targets for therapeutic interventions in prostate cancer.

描述（由申请人提供）：许多组织的细胞是极化的，共同形成了根据组织需求量身定制的构型。大多数上皮起源癌症的共同特征是正常组织结构的丧失。尽管识别涉及驱动癌症进展的信号传导途径的进步，但对转化过程中的极性如何破坏知之甚少。 David Bryant博士研究上皮极性的分子控制。他作为一名独立生物医学研究人员的长期目标是了解肿瘤形成期间上皮极性如何出现。有了该奖项，科比博士将检查ADP-核糖基化因子（ARF）GTPase家族及其调节分子（ARF“调节型”），以控制前列腺癌期间极性，因为“调节”成员在人类前列腺癌中高度表达。该K99/R00奖将使Bryant博士能够实现以下职业目标：1）前列腺生物学和人类癌症遗传学的额外培训，2）发展基因组技能，用于分析人类前列腺癌基因的表达，3）和组织病理学技术，用于分析体内人类活检和前列腺癌的小鼠模型的组织样本，以及4）发展成为成功，成功，独立的生物医学研究人员所必需的沟通，指导，授予，授予和实验室管理技能。这项研究的指导阶段将在基思·莫斯托夫（Keith Mostov）博士的指导下在加利福尼亚大学旧金山分校进行。在指导阶段，科比博士将使用遗传学，半自动化学显微镜以及正常和肿瘤前列腺上皮细胞的体外球体培养的综合方法来定义ARF调节体表达的变化，以控制前列腺腺泡形态发生的ARF调节剂表达的变化（AIM 1）。接下来，他将阐明ARF调节型和致癌途径之间的相互作用，导致耐cast割前列腺癌（AIM 2）。为了鉴定在体内前列腺癌进展过程中潜在的疾病特异性ARF调节型改变（AIM 3），Bryant博士将开始对人类患者的肿瘤和不同疾病阶段的前列腺癌模型的肿瘤进行基因组和免疫组织化学分析。博士。 Pamela Paris，Davide Ruggero（UCSF），前列腺癌基因组学和癌症遗传学专家将担任合作者和顾问。在独立阶段，科比博士将继续关注Aim 2和3，即ARF调节器控制的上皮极性的机制，以及对肿瘤中ARF调节组改变的体内分析。该奖项将使布莱恩特博士能够以快速的中等性方式检查前列腺上皮极性的分子调节，从而开发抑制ARF调节途径的选择性干预措施的发展，并有可能识别前列腺癌中治疗性干预措施的新目标。

项目成果

An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism.

• DOI: 10.1038/s41467-021-21847-4
• 发表时间: 2021-03-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Nacke M;Sandilands E;Nikolatou K;Román-Fernández Á;Mason S;Patel R;Lilla S;Yelland T;Galbraith LCA;Freckmann EC;McGarry L;Morton JP;Shanks E;Leung HY;Markert E;Ismail S;Zanivan S;Blyth K;Bryant DM
• 通讯作者: Bryant DM

The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels.

• DOI: 10.1083/jcb.202206115
• 发表时间: 2023-04-03
• 期刊: The Journal of cell biology

Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function.

• DOI: 10.1126/sciadv.abq1858
• 发表时间: 2023-02-03
• 期刊: Science advances
• 影响因子: 13.6

Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging.

• DOI: 10.1038/s41467-022-32958-x
• 发表时间: 2022-09-09
• 期刊: Nature communications
• 影响因子: 16.6

PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer.

• DOI: 10.15252/embj.2023113987
• 发表时间: 2023-09-18
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Nikolatou, Konstantina;Sandilands, Emma;Roman-Fernandez, Alvaro;Cumming, Erin M.;Freckmann, Eva;Lilla, Sergio;Buetow, Lori;McGarry, Lynn;Neilson, Matthew;Shaw, Robin;Strachan, David;Miller, Crispin;Huang, Danny T.;McNeish, Iain A.;Norman, James C.;Zanivan, Sara;Bryant, David M.
• 通讯作者: Bryant, David M.