Bidirectional cross talk between patient-derived melanoma and cancer-associated fibroblasts promotes invasion and proliferation
Bidirectional cross talk between patient-derived melanoma and cancer-associated fibroblasts promotes invasion and proliferation
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DOI：
10.1111/pcmr.12513
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发表时间：
2016-11-01
影响因子：
4.3
通讯作者：
Yoon, Charles H.
中科院分区：
文献类型：
--
作者：
Izar, Benjamin;Joyce, Cailin E.;Yoon, Charles H.
肿瘤 - 基质相互作用对上皮源性肿瘤至关重要，在基质细胞类型中，癌症相关成纤维细胞（CAFs）具有多种促进肿瘤生长、扩散和耐药的功能。然而，在恶性黑色素瘤等非上皮性肿瘤中，这些相互作用的特征尚未得到充分阐明。我们从患者的转移性病变中培养出黑色素瘤细胞和匹配的CAFs的单一培养物，通过致癌驱动因子和特征标志物的免疫印迹进行区分。对CAFs的RNA测序显示出一种同质的表观遗传程序，与上皮性癌症的特征非常相似，包括上皮 - 间质转化（EMT）的富集。单一培养的黑色素瘤CAFs表现出强大的侵袭行为，而源自患者的黑色素瘤单一培养物则几乎没有侵袭性。相反，当黑色素瘤细胞与CAFs共培养时，其侵袭性增强。反过来，当CAFs暴露于黑色素瘤条件培养基（CM）时，其增殖增加，这部分是由黑色素瘤分泌的转化生长因子 -α通过表皮生长因子受体作用于CAFs所介导的。这项研究提供的证据表明，黑色素瘤与CAFs之间的双向相互作用调节转移性黑色素瘤的进展。
Tumor-stroma interactions are critical for epithelial-derived tumors, and among the stromal cell types, cancer-associated fibroblasts (CAFs) exhibit multiple functions that fuel growth, dissemination, and drug resistance. However, these interactions remain insufficiently characterized in non-epithelial tumors such as malignant melanoma. We generated monocultures of melanoma cells and matching CAFs from patients' metastatic lesions, distinguished by oncogenic drivers and immunoblotting of characteristic markers. RNA sequencing of CAFs revealed a homogenous epigenetic program that strongly resembled the signatures from epithelial cancers, including enrichment for an epithelial-to-mesenchymal transition (EMT). Melanoma CAFs in monoculture displayed robust invasive behavior while patient-derived melanoma monocultures showed very little invasiveness. Instead, melanoma cells showed increased invasion when co-cultured with CAFs. In turn, CAFs showed increased proliferation when exposed to melanoma conditioned media (CM), mediated in part by melanoma-secreted transforming growth factor-alpha that acted on CAFs via the epidermal growth factor receptor. This study provides evidence that bidirectional interactions between melanoma and CAFs regulate progression of metastatic melanoma.