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展，但乳腺癌仍然是癌症相关死亡的第二大原因。 妇女由于乳腺癌细胞在遗传上是不稳定和异质的， 微环境（TME）具有识别新的治疗靶点的潜力。TME中的一种重要细胞因子 对于许多癌症，TGF-β1配体结合TGF-β受体以促进Smad信号传导和基因表达。 表情TGF-β信号通路在调节细胞稳态中具有明确的作用，包括 增殖、分化和凋亡。在癌症的发生和发展过程中，TGF-β信号通路 以细胞和环境特异性的方式被破坏。在乳腺癌中，TGF-β抑制肿瘤的发生，但在乳腺癌中， 已建立的癌症，促进癌症进展以增加侵袭和转移。因此，TGF-β是一种 有吸引力的癌症治疗靶点。然而，直接靶向TGF-β信号通路尚未被发现。 在临床上取得成功的部分原因是对TGF-β在癌症过程中的作用如何变化的不完全理解 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 对乳腺癌分泌组进行了蛋白质组学筛选，并鉴定了整合素结合蛋白β IGH 3 作为一种能够促进TGF-β信号传导的蛋白质。β IGH 3的CRISPR/Cas9沉默降低肿瘤生长， 乳腺癌模型中的转移。这种肿瘤进展的减少也与减少的 体内TGF-β信号传导。 我们假设β IGH 3通过促进TGF-β诱导的EMT、迁移， 和侵袭，并通过蛋白酶增加活性TGF-β1配体介导的TGF-β信号传导。 为了解决这个假设，我们提出了两个目标。目的1：确定β IGH 3是否诱导TGF-β信号传导 通过增加来自潜伏TGF β前体的成熟TGF-β1配体的活化。目标2：确定 β IGH 3是否通过促进TGF-β信号通路和TGF-β诱导的EMT增加转移 迁移、侵入和外渗。明确β IGH 3如何增加肿瘤发生的详细机制 通过TGF-β信号传导可能潜在地导致乳腺癌的新治疗靶点。