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Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis.
Journal of Cell Science ( IF 4 ) Pub Date : 2021-10-13 , DOI: 10.1242/jcs.258431
Craig E Barcus 1, 2 , Priscilla Y Hwang 1, 2, 3 , Vasilios Morikis 1, 2 , Audrey Brenot 1, 2 , Patrick Pence 1, 2 , Maria Clarke 1, 2 , Gregory D Longmore 1, 2
Affiliation  

Both tumor cell-intrinsic signals and tumor cell-extrinsic signals from cells within the tumor microenvironment influence tumor cell dissemination and metastasis. The fibrillar collagen receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) is essential for breast cancer metastasis in mouse models, and high expression of DDR2 in tumor and tumor stromal cells is strongly associated with poorer clinical outcomes. DDR2 tyrosine kinase activity has been hypothesized to be required for the metastatic activity of DDR2; however, inhibition of DDR2 tyrosine kinase activity, along with that of other RTKs, has failed to provide clinically relevant responses in metastatic patients. Here, we show that tyrosine kinase activity-independent action of DDR2 in tumor cells can support Matrigel invasion and in vivo metastasis. Paracrine actions of DDR2 in tumor cells and cancer-associated fibroblasts (CAFs) also support tumor invasion, migration and lung colonization in vivo. These data suggest that tyrosine kinase-independent functions of DDR2 could explain failures of tyrosine kinase inhibitor treatment in metastatic breast cancer patients and highlight the need for alternative therapeutic strategies that inhibit both tyrosine kinase-dependent and -independent actions of RTKs in the treatment of breast cancer. This article has an associated First Person interview with the first author of the paper.

中文翻译:

DDR2 在肿瘤细胞和癌症相关成纤维细胞中的酪氨酸激酶非依赖性作用影响肿瘤侵袭、迁移和转移。

来自肿瘤微环境内细胞的肿瘤细胞内在信号和肿瘤细胞外在信号都会影响肿瘤细胞的传播和转移。纤维状胶原蛋白受体酪氨酸激酶 (RTK) 盘基蛋白结构域受体 2 (DDR2) 对小鼠模型中的乳腺癌转移至关重要,肿瘤和肿瘤基质细胞中 DDR2 的高表达与较差的临床结果密切相关。假设 DDR2 酪氨酸激酶活性是 DDR2 转移活性所必需的;然而,DDR2 酪氨酸激酶活性的抑制以及其他 RTK 的抑制未能在转移性患者中提供临床相关的反应。在这里,我们表明 DDR2 在肿瘤细胞中的酪氨酸激酶活性独立作用可以支持 Matrigel 侵袭和体内转移。DDR2 在肿瘤细胞和癌症相关成纤维细胞 (CAF) 中的旁分泌作用也支持体内肿瘤侵袭、迁移和肺定植。这些数据表明,DDR2 的酪氨酸激酶非依赖性功能可以解释酪氨酸激酶抑制剂治疗转移性乳腺癌患者的失败,并强调需要替代治疗策略来抑制 RTK 在治疗乳腺癌中的酪氨酸激酶依赖性和非依赖性作用。癌症。本文与论文的第一作者进行了相关的第一人称采访。这些数据表明,DDR2 的酪氨酸激酶非依赖性功能可以解释酪氨酸激酶抑制剂治疗转移性乳腺癌患者的失败,并强调需要替代治疗策略来抑制 RTK 在治疗乳腺癌中的酪氨酸激酶依赖性和非依赖性作用。癌症。本文与论文的第一作者进行了相关的第一人称采访。这些数据表明,DDR2 的酪氨酸激酶非依赖性功能可以解释酪氨酸激酶抑制剂治疗转移性乳腺癌患者的失败,并强调需要替代治疗策略来抑制 RTK 在治疗乳腺癌中的酪氨酸激酶依赖性和非依赖性作用。癌症。本文与论文的第一作者进行了相关的第一人称采访。
更新日期:2021-09-03
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