Targeting lymph node metastases to prevent cancer progression

针对淋巴结转移以预防癌症进展

• 批准号: 10542290
• 负责人: TIMOTHY P PADERA
• 金额: $ 6.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-02 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542290
• 关键词: Address; Administrative Supplement; Animal Model; Antigens; Biological; Blood Vessels; Cancer Patient; Cell Line; Clinical; Complex; Data; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Elements; Equipment; Goals; Growth; Home; Immune; Immune response; Immune system; Immunology procedure; Immunosuppression; Knowledge; Laboratories; Lymphatic Metastasis; Lymphatic System; Malignant Lymph Node Neoplasm; Metastatic Neoplasm to Lymph Nodes; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Play; Positioning Attribute; Process; Prognosis; Recommendation; Regimen; Reticular Cell; Risk; Role; Site; Survival Rate; System; Systemic Therapy; Testing; Therapeutic; Translating; Tumor Immunity; Work; angiogenesis; anti-tumor immune response; cancer cell; improved; innovation; intravital imaging; intravital microscopy; lymph nodes; novel therapeutic intervention; novel therapeutics; prevent; prognostic indicator; tumor progression

This administrative supplement will support the completion of the current Aims of R01CA214913. Completing the current Aims will also provide preliminary data to respond to the Summary Statement of the A0 renewal application. These preliminary data will strengthen the A1 submission of the renewal application. Breakthroughs in our knowledge of the molecular and cellular mechanisms regulating metastasis have yet to be broadly translated into improved survival rates for patients with metastatic disease. Lymph node metastasis in a cancer patient brings with it a poorer prognosis and the recommendation for systemic therapy. However, it is unclear whether lymphatic metastases are only predictive or whether they play a role in cancer progression and the emergence of distant metastases. Evidence shows that treating lymph node metastases improves survival in some patients. The work proposed here aims to build a biological understanding of lymph node metastases in order to define their role in disease progression and identify new therapeutic interventions to improve patient survival. Recently, we have shown that lymph node metastases do not require angiogenesis to grow and do not respond to anti-angiogenic therapy. We will build upon our unique expertise by addressing why lymph node metastasis are such strong prognostic indicators and explore how lymph node metastasis drive cancer progression. Specifically, we will test the hypotheses that lymph node metastases disseminate to distant sites (Aim 1) and inhibit the ability of the immune system to develop and maintain anti-tumor immunity (Aim 2). We will accomplish our goals using innovative animal models that allow state-of-the-art intravital microscopy of spontaneous lymph node metastasis. In Aim 1, we will determine whether cancer cells utilize the fibroblastic reticular cell-lined conduit system in lymph nodes to home to blood vessels and spread to distant sites. We will attempt to block this process. In Aim 2, we will determine whether metastatic lymph nodes retain the ability to initiate immune responses to new antigens. Further, we will determine the mechanism of immune suppression in metastatic lymph nodes. We will attempt to increase immune effector function in lymph node metastases to eradicate lymph node disease and stimulate systemic anti-tumor immunity. In completing these aims, we will have better lymph node focused therapeutic options to limit the growth and spread of cancer from lymph nodes and thus provide better outcomes for patients. Dr. Padera is an expert in intravital microscopy of the lymphatic system and mechanisms of lymph node metastasis. Critical elements to achieving these goals are intravital imaging equipment, complex animal models and functional immunological assays, all available in the PI’s laboratory. In addition, the assembled team has complementary expertise that will enable them to overcome any problems that occur during the project, uniquely positioning us to address these clinically driven questions. With the completion of our studies, we will be able to better contain and eradicate lymph node metastasis to extend survival for patients with metastatic cancer.

本行政补充文件将支持完成 R01CA214913 当前的目标。 目前的Aims还将提供初步数据来回应A0更新的总结声明 这些初步数据将加强 A1 续展申请的提交。 据我们所知，调节转移的分子和细胞机制尚未得到广泛的了解 转化为癌症转移性疾病患者生存率的提高。 患者的预后较差，因此建议进行全身治疗，但尚不清楚。 淋巴转移是否仅具有预测作用，或者它们是否在癌症进展中发挥作用，以及 证据表明，治疗淋巴结转移可提高患者的生存率。 这里提出的工作旨在建立对淋巴结转移的生物学理解。 为了确定它们在疾病进展中的作用并确定新的治疗干预措施以改善患者的状况 最近，我们发现淋巴结转移不需要血管生成来生长，也不需要。 我们将利用我们独特的专业知识来解决淋巴结的原因。 转移是如此强烈的预后指标，探索淋巴结转移如何驱动癌症 具体来说，我们将测试淋巴结转移扩散到远处的进展假设。 （目标 1）并抑制免疫系统发展和维持抗肿瘤免疫力的能力（目标 2）。 将使用创新的动物模型来实现我们的目标，这些模型允许使用最先进的活体显微镜观察 在目标 1 中，我们将确定癌细胞是否利用成纤维细胞。 淋巴结中网状细胞排列的导管系统，以血管为家并扩散到远处的部位。 在目标 2 中，我们将尝试阻止这一过程，我们将确定转移淋巴结是否保留了转移的能力。 此外，我们将确定免疫抑制的机制。 我们将尝试增加淋巴结转移中的免疫效应器功能 为了实现这些目标，我们将根除淋巴结疾病并刺激全身抗肿瘤免疫力。 有更好的以淋巴结为中心的治疗方案，以限制淋巴结中癌症的生长和扩散 Padera 博士是淋巴管活体显微镜检查方面的专家。 淋巴结转移的系统和机制是实现这些目标的关键要素。 成像设备、复杂的动物模型和功能性免疫测定，所有这些都可以在 PI 中找到 此外，组建的团队拥有互补的专业知识，使他们能够克服任何困难。 项目期间出现的问题，使我们能够独特地解决这些临床驱动的问题。 我们的研究完成后，我们将能够更好地遏制和根除淋巴结转移，以延长 转移性癌症患者的生存率。

项目成果

Progression of Metastasis through Lymphatic System.

• DOI: 10.3390/cells10030627
• 发表时间: 2021-03-12
• 期刊: Cells
• 影响因子: 6
• 作者: Zhou H;Lei PJ;Padera TP
• 通讯作者: Padera TP

Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition.

• DOI: 10.1158/1078-0432.ccr-22-0486
• 发表时间: 2022-07-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research

Fate Mapping of Cancer Cells in Metastatic Lymph Nodes Using Photoconvertible Proteins.

• DOI: 10.1007/978-1-0716-1205-7_26
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Pereira ER;Kedrin D;Padera TP
• 通讯作者: Padera TP

Regeneration of collecting lymphatic vessels following injury.

损伤后集合淋巴管的再生。

• DOI: 10.21203/rs.3.rs-3025656/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Razavi,MohammadS;Lei,Pin-Ji;Amoozgar,Zohreh;Leartprapun,Nichaluk;Nadkarni,SeemantiniK;Baish,JamesW;Padera,TimothyP;Munn,LanceL
• 通讯作者: Munn,LanceL

Lymphatic muscle cells are unique cells that undergo aging induced changes.

淋巴肌细胞是经历衰老引起的变化的独特细胞。

• DOI: 10.1101/2023.11.18.567621
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Lei,Pin-Ji;Ruscic,KatarinaJ;Roh,Kangsan;Rajotte,JohannaJ;O'Melia,MeghanJ;Bouta,EchoeM;Marquez,Marla;Pereira,EthelR;Kumar,AshwinS;Arroyo-Ataz,Guillermo;Razavi,MohammadS;Zhou,Hengbo;Menzel,Lutz;Kumra,Heena;Duquette,Mark