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

描述(申请人提供)：转移性疾病是癌症死亡的主要原因。然而，正如并不是所有的原发癌症都容易转移一样，并不是所有在继发部位发现的肿瘤细胞都会危及生命。原发肿瘤部位的扩散可以发生在肿瘤发展的相对早期，而次级肿瘤部位的细胞可能具有从惰性到侵袭性恶性肿瘤的各种特性。这项建议旨在解决一个具有挑衅性的问题：我们如何确定从另一个部位的原发肿瘤中发现细胞的意义，以及可以开发哪些方法来使这一诊断在临床上有用？成功地回答这个问题将有望找到治疗肿瘤的新的跟腱，这可能是开发新疗法的基础。这项拟议研究的基本原理是基于我们的初步研究，该研究表明，人类乳腺癌异种移植瘤在全身传播细胞，这些细胞具有不同于亲代肿瘤的不同特征。鉴于我们的新见解，我们现在提议分析乳腺癌异种移植模型中的原发肿瘤和播散细胞，以寻找扩散和转移的生物标志物；通过使用微流控单细胞聚合酶链式反应分析单个细胞中的基因表达来确定这些人群中细胞的异质性；确定播散的肿瘤细胞是否有能力在移植后启动肿瘤；分析播散的肿瘤细胞在其中蓬勃发展或保持惰性的微环境的特征；以及验证传播和转移的命中率。这些研究将开启对特定表型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。了解恶性肿瘤细胞与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，将有助于更好地理解哪些播散的肿瘤细胞处于静止状态，哪些可能导致侵袭性转移。这一认识将为新的生物标记物和药理学干预奠定基础。

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.