Role for TbetaRIII Shedding in the Tumor Microenvironment

TbetaRIII 脱落在肿瘤微环境中的作用

• 批准号: 10580782
• 负责人: GERARD C BLOBE
• 金额: $ 32.76万
• 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: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580782
• 关键词: Address; Biological Process; Breast Cancer therapy; Breast Melanoma; Cathepsin G; Elastases; Environment; Event; Generations; Human; Immune; Immune system; Immunooncology; Immunotherapy; In Vitro; Leukocyte Elastase; Ligands; Malignant Neoplasms; Mediating; Pre-Clinical Model; Public Health; Role; Serine Protease; Serum; Signal Transduction; TGF beta type III receptor; Transforming Growth Factor beta; analog; cancer cell; cancer initiation; effective therapy; in vivo; insight; malignant breast neoplasm; mouse model; neutrophil; predictive marker; resistance mechanism; structural determinants; tumor; tumor growth; tumor microenvironment; tumor progression

Transforming growth factor-β (TGF-β) superfamily ligands function to suppress then promote cancer progression through mechanisms that remain to be fully defined. We have demonstrated that loss of type III TGF-β receptor (TβRIII) expression is a frequent event in human cancers. TβRIII suppresses cancer progression, in part, through ectodomain shedding that generates a soluble TβRIII (sTβRIII), which has the potential to regulate signaling throughout the tumor microenvironment (TME). While restoring TβRIII expression in cancer cells and/or sTβRIII treatment created an immunotolerant TME, the mechanisms and relative contribution of TβRIII and sTβRIII in regulating the TME, as well as their respective roles in cancer initiation and cancer progression have not been established. Here we defined the structural determinants operant in regulating TβRIII shedding, which enabled us to create: i) a TβRIII super-shedder (TβRIII-SS) and ii) a TβRIII non-shedder (TβRIII∆shed), with corresponding murine models. We have demonstrated that neutrophils may regulate TβRIII shedding. Based on these results, we hypothesize that neutrophil-mediated TβRIII loss/shedding/degradation in breast cancer and melanoma increases TGF-β superfamily signaling in the TME via loss of sTβRIII in the TME, promoting cancer progression, in part, by creating an immunotolerant TME. We further hypothesize that expressing sTβRIII or functional analogues to suppress TGF-β signaling in the TME will circumvent a mechanism of resistance and increase the efficacy of current immunotherapy approaches. We propose three Specific Aims. Aim 1: The mechanism by which neutrophils and the serine proteases, cathepsin G (CTSG) and neutrophil elastase (ELANE), mediate TβRIII shedding/degradation in the TME will be explored including defining structural determinants on TβRIII mediating shedding. Aim 2: We will define whether loss of TβRIII/sTβRIII increases TGF-β superfamily signaling in the TME to create an immunotolerant TME to promote cancer initiation or progression. Aim 3: We will define whether expressing sTβRIII or functional analogues in the TME in conjunction with current immunotherapy approaches will result in more effective therapies for breast cancer and melanoma and whether serum sTβRIII or TGF-β1 levels function as predictive biomarkers. These studies will help define the biological functions of ectodomain shedding of TβRIII in the context of the TME, providing broad impact on understanding the role of TGF-β superfamily signaling in human cancer initiation and progression, while providing proof of principle for combining anti-TGF-β signaling therapy with current immunotherapy approaches.

转化生长因子-β（TGF-β）超家族配体的功能是抑制然后促进癌症 通过尚待充分界定的机制取得进展。我们已经证明了III型糖尿病 转化生长因子β受体（TGF-β receptor，TβRIII）的表达是人类肿瘤中的常见事件。TβRIII抑制癌症 进展，部分通过胞外域脱落产生可溶性TβRIII（sTβRIII），其具有 在整个肿瘤微环境（TME）中调节信号传导的潜力。在恢复TβRIII的同时 在癌细胞中的表达和/或sTβRIII治疗产生了免疫耐受性TME，其机制和 TβRIII和sTβRIII在调节TME中的相对贡献，以及它们各自在癌症中的作用 尚未确定癌症的起始和进展。在这里，我们定义了结构决定因素 在调节TβRIII脱落中起作用，这使我们能够创建：i）TβRIII超级脱落子（TβRIII-SS）和ii） a TβRIII非散毒（TβRIII散毒），以及相应的鼠模型。我们已经证明 中性粒细胞可调节TβRIII的脱落。基于这些结果，我们假设， 乳腺癌和黑色素瘤中的TβRIII缺失/脱落/降解增加了TGF-β超家族信号传导， TME通过TME中sTβRIII的丢失，部分通过产生免疫耐受性促进癌症进展 TME。我们进一步假设，表达sTβRIII或功能类似物来抑制TGF-β信号转导， TME将绕过耐药机制并提高当前免疫疗法的功效 接近。我们提出三个具体目标。目的1：中性粒细胞和丝氨酸蛋白酶的作用机制 蛋白酶，组织蛋白酶G（CTSG）和中性粒细胞弹性蛋白酶（ELANE），介导TβRIII脱落/降解， 将探索TME，包括定义TβRIII介导脱落的结构决定因素。目标2：我们 定义TβRIII/sTβRIII的缺失是否会增加TME中TGF-β超家族的信号传导， 免疫耐受性TME促进癌症起始或进展。目标3：我们将定义是否表达 TME中的sTβRIII或功能类似物与当前的免疫治疗方法结合将导致 乳腺癌和黑色素瘤的更有效的治疗方法以及血清sTβRIII或TGF-β1水平 作为预测性生物标志物。这些研究将有助于明确胞外域的生物学功能 TME背景下TβRIII的脱落，对理解TGF-β的作用产生广泛影响 超家族信号传导在人类癌症发生和发展中的作用，同时提供了 将抗TGF-β信号传导疗法与当前的免疫疗法相结合。

项目成果

ALK1 regulates the internalization of endoglin and the type III TGF-β receptor.

• DOI: 10.1091/mbc.e20-03-0199
• 发表时间: 2021-04-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Tazat K;Pomeraniec-Abudy L;Hector-Greene M;Szilágyi SS;Sharma S;Cai EM;Corona AL;Ehrlich M;Blobe GC;Henis YI
• 通讯作者: Henis YI

TGF-β superfamily co-receptors in cancer.

• DOI: 10.1002/dvdy.338
• 发表时间: 2022-01
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Pawlak JB;Blobe GC
• 通讯作者: Blobe GC