Characterizing lymphatic micrometastases: prognostic and therapeutic implications

描述(由申请人提供) 摘要：转移仍然是癌症死亡的主要原因，但我们对转移调控的分子和细胞机制的了解的突破还没有广泛地转化为转移患者生存率的提高。挑战是如何治疗扩散到淋巴结或远处器官的癌细胞，以防止它们的生长，理想的情况是将它们从体内消除。大多数癌症治疗方法都是针对在其自然微环境中生长的原发肿瘤而开发的。然而，很明显，肿瘤细胞生长的局部微环境对肿瘤细胞的生长速度、代谢、血管形成以及最终对治疗干预的反应有很大影响。在这个NIH主任的新创新者奖中，我提议从生物学上描述从单个播种的癌细胞开始在淋巴结中转移的肿瘤细胞的生长。这项研究的动机是基本的、至关重要的问题，这些问题最终将帮助临床医生更好地管理转移性疾病：i)淋巴结转移性生长的生物学触发因素是什么？Ii)淋巴结转移是否是克隆性的，还是需要多个癌细胞才能在淋巴结内开始生长？Iii)切除仅有少量癌细胞的淋巴结是否有治疗益处？四)淋巴结转移是否会导致远处转移导致进一步扩散？为了解决这些问题，我将利用我们新开发的慢性淋巴结窗口来研究淋巴结中自发播散的癌细胞。这一创新的窗口模型克服了研究的主要障碍，使我们能够监测淋巴结转移生长的早期阶段，表征单个种子癌细胞生长的生物触发因素，确定淋巴转移是否为克隆性，并调查淋巴转移是否可以进一步扩散。通过这种方式，我们将使用新的技术以一种新的方式来解决淋巴转移的问题--在新的微环境中表征不断增长的转移。这些临床驱动的项目将产生数据，以帮助i)更好地预测结果并为淋巴结微转移疾病患者设计治疗方案，以及ii)揭示淋巴结转移肿瘤生长的潜在生物学，可能导致淋巴转移治疗的新靶点。基于我在工程学方面的基础背景，以及12年多来创新活体显微镜技术和动物模型研究肿瘤转移关键问题的经验，我是唯一有资格领导这项工作的人。我使用这些技能创造性地解决了阻碍淋巴生物学和淋巴转移关键领域研究的问题。我已经表明，我愿意挑战传统范式，并将我的工作重点放在临床相关问题上，这些问题需要基本的生物学发现来推动新的疗法。我还表明，我可以与临床医生合作，影响患者的护理。我将继续以我过去的成功为基础，设立NIH主任新创新者奖，希望能对淋巴转移患者的治疗产生积极影响。 公共卫生相关性：转移仍然是癌症死亡的主要原因，这给如何治疗扩散到淋巴结或远处器官的癌细胞提出了挑战，以防止它们的生长，并理想地将它们从体内消除。为了应对这一挑战，我将利用我们新开发的慢性淋巴结窗口来表征种子癌细胞生长的触发因素，并调查淋巴转移是否可以进一步扩散。这些临床驱动的项目将产生数据，以i)更好地预测结果并为淋巴转移患者设计治疗方案，以及ii)揭示淋巴结转移肿瘤生长的潜在生物学，导致淋巴转移治疗的新靶点。

DESCRIPTION (Provided by the applicant) Abstract: Metastasis remains the major cause of cancer mortality, but breakthroughs in our understanding of the molecular and cellular mechanisms regulating metastasis have yet to be broadly translated into improved survival rates in patients with metastatic disease. The challenge is how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. Most cancer therapies are developed against the primary tumor growing in its native microenvironment. However, it is clear that the local microenvironment in which tumor cells grow greatly affects the growth rate, metabolism, vascularization and ultimately response to therapeutic intervention. In this NIH Director's New Innovator Award, I propose to biologically characterize the growth of metastatic tumor cells in lymph nodes starting from individual seeded cancer cells. This research is motivated by basic, critically important questions that will ultimately help clinicians better manage metastatic disease: i) What are the biological triggers for metastatic growth in lymph nodes? ii) Are lymph node metastases clonal or are multiple cancer cells needed to initiate growth in the node? iii) Is there a therapeutic benefit to the removal lymph nodes with only a few cancer cells? iv) Do lymph node metastases seed distant sites leading to further dissemination? To address these questions, I will utilize our newly developed chronic lymph node window in order to study spontaneously disseminated cancer cells in the lymph node. This innovative window model overcomes a major barrier to research and allows us to monitor the earliest stages of metastatic growth in lymph nodes, characterize the biological triggers for growth from individually seeded cancer cells, determine whether lymphatic metastasis are clonal and investigate whether lymph node metastases can further disseminate. In this way, we will use novel techniques to address the problem of lymphatic metastasis in a new way-characterizing a growing metastasis in its new microenvironment. These clinically driven projects will yield data to help i) better predict outcome and design therapeutic courses for patients with micrometastatic disease in their lymph nodes, as well as ii) uncover the underlying biology of metastatic tumor growth in the lymph nodes, potentially leading to novel targets for the treatment of lymphatic metastasis. Based on my foundational background in engineering, along with over 12 years experience innovating intravital microscopy techniques and animal models to study critical problems in tumor metastasis, I am uniquely qualified to lead this effort. I have used these skills to creatively solve problems that have hindered research in critical areas of lymphatic biology and lymphatic metastasis. I have shown that I am willing to challenge conventional paradigms and keep my work focused on clinically relevant problems that need basic biological discoveries to drive new therapies. I have also shown I can work with clinicians to impact patient care. I will continue to build on my past successes with this proposed NIH Director's New Innovator Award and hopefully have a positive impact on the treatment of patients with lymphatic metastases. Public Health Relevance: Metastasis remains the major cause of cancer mortality posing the challenge of how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. To answer this challenge, I will utilize our newly developed chronic lymph node window to characterize the triggers for the growth of seeded cancer cells and investigate whether lymph node metastasis can further disseminate. These clinically driven projects will yield data to i) better predict outcome and design therapeutic courses for patients with lymphatic metastases, as well as ii) uncover the underlying biology of metastatic tumor growth in the lymph nodes, leading to novel targets for the treatment of lymphatic metastasis.