p38 signaling restricts an EMT and early dissemination in breast cancer

p38 信号传导限制乳腺癌的 EMT 和早期传播

• 批准号: 8648466
• 负责人: Kathryn Lynn Harper
• 金额: $ 3.65万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648466
• 关键词: ATF2 gene; Anoikis; Biology; Breast Epithelial Cells; Cancer Patient; Cell Fate Control; Cells; Clinical; Colorectal Cancer; Data; Detection; Disease; Ductal; E-Cadherin; Epithelial; Epithelium; Future; G1 Arrest; Genetic; Genetic Transcription; Goals; Human; Immune; In Situ; Invasive Lesion; Lesion; Lung; MAPK11 gene; MAPK14 gene; MAPK3 gene; MCF10A cells; Malignant neoplasm of pancreas; Mammary Neoplasms; Mammary gland; Mesenchyme; Modeling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Oncogene ErbB2; Organ; Pathway interactions; Patients; Phosphorylation; Population; Premalignant; Primary Neoplasm; Publishing; Recovery; Research; Residual Tumors; Residual state; Resistance; Role; SB 203580; Seeds; Signal Pathway; Signal Transduction; Site; Snails; Staging; Stress; Tumor Cell Biology; cancer recurrence; conventional therapy; effective therapy; epithelial to mesenchymal transition; high risk; improved; in vitro Model; inhibitor/antagonist; insight; malignant breast neoplasm; mammary gland development; neoplastic cell; novel; overexpression; p38 MAPK Signaling Pathway; programs; public health relevance; response; role model; slug; trait; tumor; tumor progression

DESCRIPTION (provided by applicant): Recent clinical evidence has suggested that, contrary to what was previously believed, cells are able to escape breast cancer lesions at stages when invasive disease is not present, but the mechanisms behind this remain largely unknown. These disseminated tumor cells (DTC's) lodge into secondary sites, enter a state of dormancy, escape conventional therapy, and potentially seed future metastases. Because around 90% of cancer patients die from metastatic disease, rather than as a consequence of their primary tumor is it important to develop more efficient targeted therapies for these disseminated tumor cells. The goal of the proposed research plan is to better understand the mechanisms dictating the dissemination of these cells, as well as those controlling cell fate decisions at secondary sites i order to develop more effective therapies for eradicating these populations. Preliminary evidence suggests that the stress-signaling p38¿/¿ MAPK pathway may act to restrict an Epithelial to Mesenchymal Transition (EMT) and consequentially early dissemination from pre-malignant lesions. This regulatory mechanism may be lost in ErbB2+ MECs potentially through activated Wnt signaling. This project will investigate (1) how p38¿/¿ inhibits EMT and early dissemination in pre-malignant lesions, (2) the mechanism by which ErbB2 acts to inhibit p38¿/¿ signaling and (3) whether the EMT program persists in early DTCs and whether p38¿/¿ signaling still influences DTC cell fate in target organs. The proposed research plan will provide novel insight into the role of these signaling pathways in early dissemination and cell fate decisions during early stages of breast cancer progression. Completion of these aims will improve our understanding of the biology behind early dissemination, help to identify patients at higher risk of metastatic disease and potentially identify new targeted therapies for residual disease.

描述（由申请人提供）：最近的临床证据表明，与之前认为的相反，细胞能够在浸润性疾病不存在的阶段逃离乳腺癌病变，但其背后的机制在很大程度上仍然未知。这些弥散性肿瘤细胞（DTC）进入继发部位，进入休眠状态，逃避常规治疗，并可能为未来的转移播下种子。由于大约90%的癌症患者死于转移性疾病，而不是原发肿瘤，因此针对这些弥散性肿瘤细胞开发更有效的靶向治疗方法非常重要。提出的研究计划的目标是更好地了解这些细胞传播的机制，以及那些控制次要部位细胞命运决定的机制，以便开发更有效的治疗方法来根除这些群体。初步证据表明，应激信号通路p38 / MAPK可能会限制上皮细胞向间充质细胞的转化（EMT），从而限制癌前病变的早期传播。这种调节机制可能在ErbB2+ mec中通过激活Wnt信号而丢失。该项目将研究(1)p38如何抑制EMT和恶性病变前的早期传播，(2)ErbB2抑制p38信号传导的机制，(3)EMT程序是否在早期DTC中持续存在，以及p38信号传导是否仍然影响靶器官中DTC细胞的命运。提出的研究计划将为这些信号通路在乳腺癌进展早期传播和细胞命运决定中的作用提供新的见解。完成这些目标将提高我们对早期传播背后的生物学的理解，有助于识别转移性疾病风险较高的患者，并可能确定针对残留疾病的新靶向治疗方法。