(PQC4) Fate of cells disseminating from human breast cancer xenografts

(PQC4) 从人乳腺癌异种移植物中传播的细胞的命运

基本信息

批准号：
9086309
负责人：
ZENA WERB
金额：
$ 32.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086309
关键词：
Address Biological Markers Biological Models Blood Circulation Breast Cancer Cell Breast Cancer Model Breast Cancer therapy Breast cancer metastasis Cause of Death Cell Survival Cells Cessation of life Characteristics Complex Decision Making Development Diagnosis Disease Distant ERBB2 gene Evaluation Fostering Gene Expression Goals Growth Health Heterogeneity Human Indolent Intervention Knowledge Lead Learning Life Malignant - descriptor Malignant Neoplasms Methods Molecular Molecular Profiling Monitor Mus Mutation Neoplasm Metastasis Non-Malignant Organ Outcome Parents Pathway interactions Patients Phenotype Population Primary Neoplasm Property Regulation Research Site Staging Testing Therapeutic Tissues Transplantation Woman Xenograft Model Xenograft procedure anticancer research base cancer biomarkers cancer cell cancer subtypes design innovation insight malignant breast neoplasm neoplastic cell new therapeutic target novel novel strategies novel therapeutics outcome forecast research clinical testing research study tool triple-negative invasive breast carcinoma tumor tumor progression unnecessary treatment

项目摘要

DESCRIPTION (provided by applicant): Metastatic disease is the major cause of death from cancer. However, just as not all primary cancers are prone to metastasize, not all tumor cells found at secondary sites are life-threatening. Dissemination from a primary tumor site can occur relatively early in tumor development, and cells at secondary sites may have properties that range from indolence to aggressive malignancy. This proposal is designed to address the provocative question "How do we determine the significance of finding cells from a primary tumor at another site and what methods can be developed to make this diagnosis clinically useful?" successfully answering this question would be expected to identify new Achilles' heels for tumors which could be the basis for developing novel therapeutics. The rationale for the proposed research is based on our preliminary studies showing that human breast cancer xenografts disseminate cells around the body and that these cells have distinct profiles that differ from the parent tumor. Given our novel insights, we now propose to analyze primary tumors and disseminated cells from human xenograft models of breast cancer for biomarkers of dissemination and metastasis; determine the heterogeneity of the cells in these populations by characterizing gene expression in single cells using micro-fluidic single cell PCR analysis; determine whether the disseminated tumor cells have the ability to initiate tumors upon transplantation; analyze the characteristics of the microenvironment of the disseminated tumor cells in which they flourish or remain indolent; and validate the hits for dissemination and metastasis. These studies will open up further studies with transplant of single cells of specific phenotypes, to learn which changes are crucial for metastasis. Understanding the molecular mechanisms of this complex interplay between malignant cancer cells and their surrounding non-malignant stroma represents one of the major challenges in cancer research, which once understood, will foster a better understanding of which disseminated tumor cells are quiescent and which are likely to give rise to metastases aggressively. This understanding will form the basis for new biomarkers and pharmacological interventions.

描述（由申请人提供）：转移性疾病是癌症死亡的主要原因。然而，正如并非所有原发性癌症都易于转移一样，并非所有在继发部位发现的肿瘤细胞都会危及生命。原发肿瘤部位的播散可能发生在肿瘤发展的相对早期，而继发部位的细胞可能具有从惰性到侵袭性恶性肿瘤的特性。该提案旨在解决一个具有争议性的问题：“我们如何确定从另一个部位的原发性肿瘤中发现细胞的重要性，以及可以开发什么方法来使这种诊断在临床上有用？”成功回答这个问题有望找出肿瘤新的致命弱点，这可能成为开发新疗法的基础。拟议研究的基本原理基于我们的初步研究，该研究表明人类乳腺癌异种移植物将细胞散布到身体各处，并且这些细胞具有与母体肿瘤不同的独特特征。鉴于我们的新见解，我们现在建议分析来自人类乳腺癌异种移植模型的原发性肿瘤和播散细胞，以寻找播散和转移的生物标志物；通过使用微流体单细胞 PCR 分析表征单细胞中的基因表达，确定这些群体中细胞的异质性；确定播散的肿瘤细胞是否具有移植后引发肿瘤的能力；分析播散性肿瘤细胞生长或保持惰性的微环境特征；并验证传播和转移的命中。这些研究将开启对特定表型的单细胞移植的进一步研究，以了解哪些变化对于转移至关重要。了解恶性癌细胞与其周围非恶性基质之间这种复杂相互作用的分子机制是癌症研究的主要挑战之一，一旦了解这一点，将有助于更好地了解哪些播散性肿瘤细胞处于静止状态，哪些可能会发生转移。积极引起转移。这种理解将构成新生物标志物和药理学干预措施的基础。