Yegodayev Ksenia M, Novoplansky Ofra, Golden Artemiy, Prasad Manu, Levin Liron, Jagadeeshan Sankar, Zorea Jonathan, Dimitstein Orr, Joshua Ben-Zion, Cohen Limor, Khrameeva Ekaterina, Elkabets Moshe
The Shraga Segal Department of Microbiology, Immunology, and Genetics, 84105 Beer-Sheva, Israel.
Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
Cancers (Basel). 2020 Feb 3;12(2):339. doi: 10.3390/cancers12020339.
Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (Cetuximab-PDX). However, in PDXs that were extremely sensitive to cetuximab (Cetuximab-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of Cetuximab-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of Cetuximab-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.
大多数头颈癌（HNC）患者对西妥昔单抗耐药，西妥昔单抗是一种针对表皮生长因子受体的抗体。已知这种治疗耐药性部分由肿瘤细胞周围的基质细胞介导；然而，这种耐药表型背后的机制仍不清楚。为了以无偏见的方式确定西妥昔单抗耐药的机制，我们对源自HNC患者的异种移植瘤（PDX）进行了RNA测序（RNA-seq）。比较西妥昔单抗治疗前后HNC-PDX的基因表达表明，在接受西妥昔单抗治疗后病情进展的PDX（西妥昔单抗-PDX）的基质细胞中，转化生长因子-β（TGF-β）信号通路上调。然而，在对西妥昔单抗极度敏感的PDX（西妥昔单抗-PDX）中，TGF-β通路在基质区室中下调。PDX的组织病理学分析表明，在西妥昔单抗-PDX的癌症相关成纤维细胞（CAF）中检测到TGF-β激活。这些TGF-β激活的CAF足以在体外和体内限制西妥昔单抗的疗效。此外，使用SMAD3抑制剂SIS3阻断TGF-β通路可增强西妥昔单抗的疗效，并阻止西妥昔单抗-PDX的进展。总之，我们的研究结果表明，TGF-β激活的CAF在限制HNC中西妥昔单抗的疗效方面发挥作用。
