Role for TbetaRIII Shedding in the Tumor Microenvironment

TbetaRIII 脱落在肿瘤微环境中的作用

基本信息

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
项目类别：
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

项目摘要

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) 超家族配体具有抑制然后促进癌症的功能我们已经证明了 III 型的丧失是通过哪些机制进行的。 TGF-β 受体 (TβRIII) 表达是人类癌症中的常见现象，TβRIII 可以抑制癌症。进展部分是通过胞外域脱落产生可溶性 TβRIII (sTβRIII)，它具有在恢复 TβRIII 的同时调节整个肿瘤微环境 (TME) 的信号传导潜力。癌细胞中的表达和/或 sTβRIII 治疗创造了免疫耐受的 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癌症的发生和进展尚未确定。在此我们定义了结构决定因素。调节 TβRIII 脱落的操作，这使我们能够创建：i) TβRIII 超级脱落者 (TβRIII-SS) 和 ii) TβRIII 非脱落者（TβRIIIΔshed），以及相应的小鼠模型我们已经证明了这一点。基于这些结果，我们发现中性粒细胞可能调节 TβRIII 脱落。乳腺癌和黑色素瘤中的 TβRIII 丢失/脱落/降解会增加 TGF-β 超家族信号传导 TME 通过 TME 中 sTβRIII 的缺失，促进癌症进展，部分是通过产生免疫耐受 TME。我们进一步支持表达 sTβRIII 或功能类似物来抑制 TGF-β 信号传导。 TME 将规避耐药机制并提高当前免疫疗法的疗效我们提出了三个具体目标目标 1：中性粒细胞和丝氨酸的作用机制。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。定义 TβRIII/sTβRIII 的缺失是否会增加 TME 中的 TGF-β 超家族信号传导，从而创建免疫耐受 TME 促进癌症发生或进展目标 3：我们将确定是否表达。 TME 中的 sTβRIII 或功能类似物与当前的免疫治疗方法相结合将导致乳腺癌和黑色素瘤的更有效治疗方法，无论是血清 sTβRIII 还是 TGF-β1 水平这些研究将有助于确定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人类癌症发生和进展中的超家族信号传导，同时提供原理证明将抗 TGF-β 信号传导疗法与当前的免疫疗法相结合。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.