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.

本行政补充将支持完成R01CA214913的当前目标。完成

项目成果

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

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

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

Inducible Nitric Oxide Synthase and CD11b+Gr1+ Cells Impair Lymphatic Contraction of Tumor-Draining Lymphatic Vessels.

诱导型一氧化氮合酶和 CD11b Gr1 细胞会损害肿瘤引流淋巴管的淋巴收缩。

• DOI: 10.1089/lrb.2018.0013
• 发表时间: 2019
• 期刊: Lymphatic research and biology
• 影响因子: 1.4
• 作者: Liao,Shan;Bouta,EchoeM;Morris,LindaM;Jones,Dennis;Jain,RakeshK;Padera,TimothyP
• 通讯作者: Padera,TimothyP