Mechanisms of Src activation and its role in latent bone metastasis of breast and

Src激活机制及其在乳腺和骨潜伏骨转移中的作用

• 批准号: 7950370
• 负责人: Xiang Zhang
• 金额: $ 16.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950370
• 关键词: Accounting; Adjuvant Therapy; Androgens; Antiestrogen Therapy; Apoptosis; Arts; Award; Bachelor' s Degree; Bioinformatics; Biological; Biology; Bone Marrow; Breast; Breast Cancer Cell; CXCL12 gene; Cancer Biology; Cancer Patient; Cells; Classification; Clinical; Clinical Oncology; Clinical Trials; Clonal Evolution; Collaborations; Communities; Complement; Core Facility; Couples; Data; Data Set; Dependence; Development; Doctor of Philosophy; Drug resistance; ERBB2 gene; Environment; Epidermal Growth Factor; Estrogen Antagonists; Estrogen Receptor Status; Estrogen Receptors; Estrogen Therapy; Estrogens; Excision; Exhibits; Experimental Models; FDA approved; Faculty; Fostering; Future; Gene Expression; Goals; Grant; Hand; Human; Human Pathology; IGF1 gene; Immunodeficient Mouse; Implant; Knowledge; Laboratories; Lead; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Mentors; Metastatic Neoplasm to the Bone; Mission; Molecular Biology; Molecular Profiling; Neoplasm Metastasis; Organ Specificity; Pathway interactions; Play; Positioning Attribute; Primary Neoplasm; Process; Public Health; RNA Interference; RNA Splicing; Reagent; Recurrence; Relapse; Research; Research Personnel; Resistance; Resistance development; Role; Sampling; Scientist; Series; Signal Transduction; Site; Solid Neoplasm; Staging; TNFSF10 gene; Tamoxifen; Techniques; Technology; Testing; Therapeutic; Thinking; Training; Training Activity; Tropism; Universities; Writing; Xenograft Model; base; bone; cancer cell; cancer type; career; career development; clinical practice; clinically relevant; cytokine; deprivation; design; experience; hormone therapy; human data; inhibitor/antagonist; insight; interest; mRNA Precursor; malignant breast neoplasm; neoplastic cell; novel; novel therapeutics; overexpression; prevent; programs; public health relevance; research study; response; responsible research conduct; skills; success; therapeutic target; therapy resistant; translational study; tumor; tumor progression; v-src Oncogenes

DESCRIPTION (provided by applicant): Metastasis represents a major threat to the lives of cancer patients. Although most solid tumors can be surgically removed, metastatic relapses may occur years or decades later, usually accompanied with resistance to adjuvant therapies. My long-term goal is to understand the biological mechanism underlying metastasis latency and the associated drug-resistance. The immediate aims proposed in this application focus on the role of an oncogene, Src, in mediating latent bone metastasis of breast and prostate cancers. I have recently found that Src activity associates with latent bone metastasis in gene expression datasets of breast tumors. In experimental models, inhibition of Src decreased survival of cancer cells in the bone marrow. Mechanistically, I showed that Src mediates survival response of cancer cells to cytokines that are specifically enriched in bone metastases. These results indicated that Src plays an important role in metastasis latency and have provoked considerable interests of clinicians at Memorial Sloan Kettering Cancer Center (MSKCC). A clinical trial that aims to determine the effect of FDA-approved Src inhibitors on the level of cancer cells in the bone marrow is being designed and will soon be carried out. The experiments proposed in this application are based on the above finding as well as some provocative preliminary data. I plan to reveal mechanisms that activate Src and consequently confer cancer cells ability to survive in the bone marrow. Moreover, I will also explore the possibility that Src connects latent metastasis with resistance to adjuvant therapies in specific subtypes of breast tumors. I will then extend my studies to prostate cancer, another cancer type that exhibits a strong proclivity to develop latent bone metastasis. The main approach I will employ to study metastasis will be xenograft models (implanting human tumor cells to immunodeficient mice). RNAi technology and pharmacological inhibition will be used to intervene the activities of Src and related molecules. I believe the research described here is timely, feasible and important for the public health. The Pathway to Independence Award would greatly facilitate my success in performing these studies by providing opportunities for additional training and a smooth career transition. I obtained my bachelor degree with the highest honors from Fudan University in 2000. In the same year I entered Columbia University to pursue a PhD degree in biology. My graduate training focused on pre-mRNA splicing, a fundamental process in gene expression. I took an integrative approach combining the power of bioinformatics and molecular biology. Such approach not only led to a series of important findings but also equipped me with interdisciplinary expertise. In 2006, I graduated from Columbia University and was awarded "Distinction to the Dissertation". I then joined Dr. Joan Massagui's lab and started my postdoctoral career in the field of cancer biology and metastasis. In the past three years, I have complemented my previous skills by absorbing a large set of technical and conceptual approaches to metastasis research. I have performed a series of sophisticated analyses in gene expression profiles or array CGH data of human tumors and made several important discoveries including the Src-metastasis latency connection. Moreover, I have been exposed to a large amount of knowledge of clinical oncology and human pathology. All of this experience has fostered my development into a cancer biologist with broad expertise and integrative thinking. My future career goal is to obtain a faculty position and establish an independent research program on metastasis. In seeking a K99/R00 award, I aim to gain more comprehensive skills in studying metastasis and to successfully extend my research to the field of prostate cancer. To this end, I will continue my training in Dr. Massgue's Lab, one of the world-leading programs in metastasis research. In addition, I have also invited Drs. Larry Norton and Neal Rosen to be my co-mentors. Their expertise in clinical oncology and translational studies will help me to direct the project toward a clinical relevant angel. To obtain clinical samples essential for my research goals, I have established collaboration with Dr. Edi Brogi and Dr. John Foekens. A major challenge during my career development will be to extend the research to prostate cancer, which requires specific techniques and insights. Drs. Charles Sawyers and Howard Scher have agreed to help me establish this expertise. I will gain hands-on experience and obtain relevant reagents from their laboratories. Moreover, they are willing to be potential collaborators after I gain dependence. My career transition will also involve various training activities including Responsible Conduct of Research, mentoring, grant writing, presentation, and lab management. All of this training as well as my scientific research will take place at MSKCC, an ideal environment with state-of-art core facilities and highly interactive scientific community. MSKCC provides a robust bridge between scientific research and clinical practice and gathers outstanding scientists and clinicians. At this transitional stage of my career, I will continue to benefit from this research-intensive and clinical-oriented environment. The K99/R00 award would foster my interaction with the diverse expertise in this community, facilitate my maturation as an independent researcher and enable a smooth transition toward the next stage of my career. PUBLIC HEALTH RELEVANCE: In certain cancers, metastasis may occur years or decades after the removal of primary tumors, usually accompanied by resistance to adjuvant therapies. The proposed study will investigate the activation mechanisms of Src and explore its role in latent bone metastasis and therapeutic resistance in breast and prostate cancers. Because of the availability of FDA-approved Src inhibitors, this study will carry significant clinical implications and may suggest novel therapeutic strategies that can be immediately subject to clinical trials.

描述（由申请人提供）：转移是对癌症患者生命的主要威胁。虽然大多数实体瘤可以手术切除，但转移性复发可能在数年或数十年后发生，通常伴有对辅助治疗的抵抗。我的长期目标是了解转移潜伏期和相关耐药性的生物学机制。在本应用中提出的直接目标集中在癌基因Src在介导乳腺癌和前列腺癌的潜在骨转移中的作用。我最近在乳腺肿瘤的基因表达数据集中发现Src活性与潜在骨转移有关。在实验模型中，抑制Src降低了骨髓中癌细胞的存活。在机制上，我发现Src介导癌细胞对骨转移中特异性富集的细胞因子的生存反应。这些结果表明，Src在转移潜伏期中起重要作用，引起了纪念斯隆-凯特琳癌症中心（MSKCC）临床医生的极大兴趣。一项旨在确定fda批准的Src抑制剂对骨髓中癌细胞水平影响的临床试验正在设计中，并将很快进行。

项目成果

Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.

• DOI: 10.1016/j.ccr.2012.08.013
• 发表时间: 2012-11-13
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Calon A;Espinet E;Palomo-Ponce S;Tauriello DV;Iglesias M;Céspedes MV;Sevillano M;Nadal C;Jung P;Zhang XH;Byrom D;Riera A;Rossell D;Mangues R;Massagué J;Sancho E;Batlle E
• 通讯作者: Batlle E