Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2.
Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2.
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DOI：
10.1158/2159-8290.cd-13-0005
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发表时间：
2013-12
期刊：
影响因子：
28.2
通讯作者：
Weeraratna AT
中科院分区：
文献类型：
--
作者：
O'Connell MP;Marchbank K;Webster MR;Valiga AA;Kaur A;Vultur A;Li L;Herlyn M;Villanueva J;Liu Q;Yin X;Widura S;Nelson J;Ruiz N;Camilli TC;Indig FE;Flaherty KT;Wargo JA;Frederick DT;Cooper ZA;Nair S;Amaravadi RK;Schuchter LM;Karakousis GC;Xu W;Xu X;Weeraratna AT
黑色素瘤生物学中的一个新兴概念是动态的适应性表型转换，其中细胞从高度增殖、侵袭性差的表型转换为高度侵袭、增殖性差的表型。这种转换不仅对转移有重要意义，而且对治疗耐药性也有重要意义。我们证明，表型转换和随后的阻力可以通过参与非经典Wnt5A信号通路，ROR1和ROR2的受体表达的变化来指导。ROR1和ROR2在黑色素瘤中反向表达，并相互负调节。此外，缺氧引发ROR1阳性黑色素瘤向更具侵袭性的ROR2阳性表型转变。值得注意的是，这种受体转换诱导对BRAF抑制剂的敏感性降低10倍。在接受BRAF抑制剂Vemurafenib治疗的黑色素瘤患者中，Wnt5A表达与临床反应和治疗抗性相关。这些数据强调了这样一个事实，即引导转移进展的机制可能与介导治疗耐药性的机制有关。
An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.