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

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是危及生命的。从原发肿瘤部位的扩散可以在肿瘤发展的相对早期发生，并且继发部位的细胞可以具有从惰性到侵袭性恶性肿瘤的性质。该提案旨在解决一个具有争议性的问题：“我们如何确定在另一个部位发现原发性肿瘤细胞的意义，以及可以开发什么方法来使这种诊断在临床上有用？”“成功回答这个问题将有望确定肿瘤的新的致命弱点，这可能是开发新疗法的基础。这项研究的基本原理是基于我们的初步研究，这些研究表明，人类乳腺癌异种移植物将细胞散布在全身，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，我们现在提出分析来自乳腺癌的人类异种移植模型的原发性肿瘤和播散细胞的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来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在移植后引发肿瘤的能力;分析扩散的肿瘤细胞的微环境的特征，在其中它们蓬勃发展或保持惰性;并验证扩散和转移的命中。这些研究将开启对特定表型的单细胞移植的进一步研究，以了解哪些变化对转移至关重要。了解恶性癌细胞及其周围非恶性间质之间这种复杂相互作用的分子机制是癌症研究中的主要挑战之一，一旦了解，将促进更好地了解哪些播散性肿瘤细胞是静止的，哪些可能引起侵袭性转移。这种理解将成为新的生物标志物和药物干预的基础。

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.