TGFBI in the breast cancer microenvironment promotes TGF-B signaling to increase tumor progression

乳腺癌微环境中的 TGFBI 促进 TGF-B 信号传导，加速肿瘤进展

• 批准号: 10005812
• 负责人: Armando L Corona
• 金额: $ 3.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005812
• 关键词: Address; Apoptosis; Attention; Binding; Binding Proteins; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Model; Breast Cancer Patient; CRISPR/Cas technology; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinic; Co-Immunoprecipitations; Complex; Data; Disease; Endothelial Cells; Epithelial; Epithelium; Event; Extracellular Matrix Proteins; Extravasation; Feedback; Gene Expression; Genes; Goals; Homeostasis; Hormone Responsive; In Vitro; Injections; Integrin Binding; Integrins; Invaded; Lead; Life; Ligand Binding; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mesenchymal; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Modeling; Mutagenesis; Neoplasm Metastasis; Nuclear; Organ; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Phosphorylation; Phosphotransferases; Play; Primary Neoplasm; Process; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Research; Role; Signal Pathway; Signal Transduction; TGF Beta Signaling Pathway; TGFBI gene; TGFBR2 gene; Tail; Time; Tissues; Toxic effect; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Transitional Epithelium; Woman; advanced breast cancer; base; breast cancer progression; cancer cell; cancer initiation; cancer therapy; cytokine; early phase clinical trial; epithelial to mesenchymal transition; genetic corepressor; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; insight; malignant breast neoplasm; migration; new therapeutic target; novel; receptor; therapeutic target; transcription factor; tumor growth; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

SCOPE OF WORK Despite advances in therapy, breast cancer remains the second leading cause of cancer related deaths in women. As breast cancer cells are genetically unstable and heterogeneous, focusing on the tumor microenvironment (TME) has the potential to identify new therapeutic targets. One important cytokine in the TME for many cancers is the TGF-β1 ligand that binds TGF-β receptors to promote Smad signaling and gene expression. The TGF-β signaling pathway has well established roles in regulating cellular homeostasis, including proliferation, differentiation and apoptosis. During cancer initiation and progression, the TGF-β signaling pathway is disrupted in a cell and context specific manner. In breast cancer, TGF-β suppresses tumor initiation, but in established cancers, promotes cancer progression to increase invasion and metastasis. As such, TGF-β is an attractive cancer therapeutic target. However, targeting the TGF-β signaling pathway directly has not been successful in the clinic partially due to an incomplete understanding of how TGF-β’s role changes during cancer progression. To gain insight into factors that may regulate TGF-β signaling in the tumor microenvironment, we performed a proteomic screen of the breast cancer secretome and identified the integrin binding protein βIGH3 as a protein able to promote TGF-β signaling. CRISPR/Cas9 silencing of βIGH3 decreases tumor growth and metastasis in a breast cancer model. This decrease in tumor progression was also associated with decreased TGF-β signaling in vivo. We hypothesize that βIGH3 increases breast cancer progression by promoting TGF-β-induced EMT, migration and invasion, with effects on TGF-β signaling mediated by increasing active TGF-β1 ligand through proteases. To address this hypothesis, we propose two aims. Aim 1: To establish whether βIGH3 induces TGF-β signaling by increasing the activation of mature TGF-β1 ligand from the latent-TGFβ precursor. Aim 2: To determine whether βIGH3 increases metastasis by promoting TGF-β signaling and TGF-β induced EMT associated migration, invasion and extravasation. Defining the detailed mechanism of how βIGH3 increases tumorigenesis through TGF-β signaling could potentially lead to a new therapeutic target in breast cancer.

工作范围 尽管在治疗方面取得了进步，但乳腺癌仍然是癌症与癌症相关死亡的第二大原因 女性。由于乳腺癌细胞在遗传上不稳定和异质性，因此着重于肿瘤 微环境（TME）有可能识别新的治疗靶标。 TME中的一个重要的细胞因子 对于许多癌症而言，TGF-β1配体结合TGF-β受体以促进SMAD信号和基因 表达。 TGF-β信号传导途径在调节细胞稳态中具有很好的作用，包括 增殖，分化和凋亡。在癌症开始和进展过程中，TGF-β信号通路 以特定于单元格和上下文的方式被破坏。在乳腺癌中，TGF-β抑制了肿瘤的启动，但在 建立的癌症，促进癌症的进展以增加侵袭和转移。因此，TGF-β是 有吸引力的癌症治疗靶标。但是，直接靶向TGF-β信号通路 由于对TGF-β在癌症中的作用如何变化的不完全了解，因此在诊所取得了成功的部分成功 进展。为了深入了解可能调节肿瘤微环境中TGF-β信号传导的因素，我们 进行了乳腺癌分泌组的蛋白质组学筛选，并确定了整联蛋白结合蛋白β33 作为蛋白质可以促进TGF-β信号传导。 CRISPR/cas9沉默β3降低了肿瘤的生长和 乳腺癌模型中的转移。肿瘤进展的减少也与减少有关 体内TGF-β信号传导。 我们假设β3通过促进TGF-β诱导的EMT，迁移来增加乳腺癌的进展 和入侵，对通过蛋白酶增加活性TGF-β1配体介导的TGF-β信号传导的影响。 为了解决这一假设，我们提出了两个目标。目标1：确定β33是否诱导TGF-β信号传导 通过增加潜在-TGFβ前体的成熟TGF-β1配体的激活。目标2：确定 β3是否通过促进TGF-β信号传导和TGF-β诱导的EMT相关的EMT是否增加转移 迁移，入侵和奢侈。定义β3如何增加肿瘤发生的详细机制 通过TGF-β信号传导可能会导致乳腺癌的新治疗靶点。