Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.
Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.
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放射治疗诱导的ADAM 10驱动胰腺癌的纤维化、耐药性和上皮-间质转化
DOI：
10.1158/0008-5472.can-20-3892
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发表时间：
2021-06-15
期刊：
影响因子：
11.2
通讯作者：
Karam SD
中科院分区：
文献类型：
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作者：
Mueller AC;Piper M;Goodspeed A;Bhuvane S;Williams JS;Bhatia S;Phan AV;Van Court B;Zolman KL;Peña B;Oweida AJ;Zakem S;Meguid C;Knitz MW;Darragh L;Bickett TE;Gadwa J;Mestroni L;Taylor MRG;Jordan KR;Dempsey P;Lucia MS;McCarter MD;Del Chiaro M;Messersmith WA;Schulick RD;Goodman KA;Gough MJ;Greene CS;Costello JC;Neto AG;Lagares D;Hansen KC;Van Bokhoven A;Karam SD
间质纤维化激活胰腺导管腺癌 (PDAC) 中的促生存和促上皮间质转化 (EMT) 途径。在接受新辅助立体定向放射治疗 (SBRT) 治疗的患者肿瘤中，我们发现纤维化、细胞外基质 (ECM) 和 EMT 基因特征上调，这可能会导致治疗耐药和肿瘤侵袭。分子、功能和翻译分析确定了两种细胞表面蛋白，解整合素和金属蛋白酶 10 (ADAM10) 和 ephrinB2，作为放疗后纤维化和肿瘤进展的驱动因素。 RT 导致肿瘤细胞中 ADAM10 表达增加，导致 ephrinB2 裂解，这也在血浆中检测到。 ADAM10 的药理学或基因靶向可减少放疗诱导的纤维化和组织张力、肿瘤细胞迁移和侵袭，使原位肿瘤对放射杀伤敏感并延长小鼠的生存期。成纤维细胞中 ADAM10 的抑制和 ephrinB2 的基因消除降低了 RT 后肿瘤细胞的转移潜力。 EphrinB2 FC 蛋白刺激肿瘤细胞逆转了 ADAM10 消融导致的肿瘤细胞侵袭减少。这些发现代表了 PDAC 适应模型，可以解释放射治疗后的耐药性和转移，并确定增强放疗疗效的靶向途径。
Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy.