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Role of splice- and translation-variants of the cysteine protease cathepsin L in the progression and metastasis of mammary cancer

半胱氨酸蛋白酶组织蛋白酶 L 的剪接和翻译变体在乳腺癌进展和转移中的作用

基本信息

批准号：
233628567
负责人：
Professor Dr. Thomas Reinheckel
金额：
--
依托单位：
Institut für Molekulare Medizin und Zellforschung
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/233628567?language=en
关键词：
Role splice translation variants cysteine

项目摘要

Proteolytic enzymes are versatile players in the growth and dissemination of malignant tumors. We have recently shown that overexpression of cathepsin L promotes formation of lung metastasis in the MMTV-PyMT mouse model for metastasizing breast cancer. In addition we established that cathepsin L biosynthesis is maintained at high level even under tumor-relevant stress conditions. In the future we want to elucidate the intracellular tumor promoting functions of cathepsin L. Of special interest is the possible link of the lysosomal protease to a central ceck point of cell growth, i.e. the mTOR pathway. Thus, this project aims to elucidate how the lysosomal protease cathepsin L affects tumor growth and metastasis by analysis of breast cancers in mouse models and human breast cancer cell lines. As preparatory work we generated a transgenic mouse allowing for selective ablation of cathepsin L in various cell types residing in the cancer. This mouse line has been crossed to the MMTV-PyMT mouse model of metastasizing breast cancer and tumor progression and metastatic dissemination will be systematically studied. Functional analysis of primary and immortalized cell cultures derived from the mouse models and expression studies in primary breast cancer specimens of patients complement the genetic animal studies.The following key questions will be addressed: 1) Cell type selective ablation of cathepsin L in the cancer cells of the MMTV-PyMT breast cancer model 2) mTOR activity, lysosomal biogenesis and autophagy will be studied upon cathepsin inhibition in tumor-relevant cell culture conditions. 3) Biochemical analysis of purified cathepsin L-deficient lysosomes. 4) Functional validation of the novel molecular links in vivo.

蛋白水解酶在恶性肿瘤的生长和传播中起着多种作用。我们最近发现，在MMTV-PyMT转移性乳腺癌小鼠模型中，组织蛋白酶L的过表达促进了肺转移的形成。此外，我们确定组织蛋白酶L的生物合成即使在肿瘤相关的应激条件下也保持在高水平。在未来，我们希望阐明组织蛋白酶l的细胞内肿瘤促进功能。特别感兴趣的是溶酶体蛋白酶与细胞生长的中心检查点，即mTOR途径的可能联系。因此，本项目旨在通过对小鼠乳腺癌模型和人乳腺癌细胞系的分析，阐明溶酶体蛋白酶组织蛋白酶L如何影响肿瘤的生长和转移。作为准备工作，我们产生了一种转基因小鼠，允许选择性消融驻留在癌症中的各种细胞类型的组织蛋白酶L。该小鼠系已被交叉到转移性乳腺癌的MMTV-PyMT小鼠模型中，肿瘤进展和转移性传播将被系统地研究。来源于小鼠模型的原代和永生化细胞培养物的功能分析以及原发性乳腺癌患者标本的表达研究补充了遗传动物研究。将解决以下关键问题：1)MMTV-PyMT乳腺癌模型癌细胞中组织蛋白酶L的细胞类型选择性消融2)在肿瘤相关细胞培养条件下，组织蛋白酶抑制mTOR活性，溶酶体生物发生和自噬将被研究。纯化组织蛋白酶l缺陷溶酶体的生化分析。4)新型分子链在体内的功能验证。