Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics
Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics
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DOI：
10.1038/s41388-022-02288-9
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发表时间：
2022-04-13
期刊：
影响因子：
8
通讯作者：
Enomoto, Atsushi
中科院分区：
文献类型：
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作者：
Iida, Tadashi;Mizutani, Yasuyuki;Enomoto, Atsushi
在胰腺导管腺癌(PDAC)中，以前试图去除肿瘤相关成纤维细胞(CAF)或抑制其增殖的治疗尝试在小鼠或患者身上都不成功。因此，CAF可以是抑癌或异质的，具有截然不同的抑癌和促癌CAF(分别为rCAF和pCAF)。在这里，我们证明了通过遗传和药物方法在CAF中诱导糖基化磷脂酰肌醇锚定蛋白Meflin的表达，这是一种RCAF特异性标记，提高了小鼠PDAC的化疗敏感性。化学文库筛选发现，Am80是一种人工合成的非天然维甲酸，是一种有效地诱导CAF中Meflin表达的试剂。AM80增加了PDAC对化疗药物的敏感性，并伴随着肿瘤血管面积和肿瘤内药物输送的增加。从机制上讲，Meflin通过与赖氨酰氧化酶相互作用来抑制其胶原交联性，从而参与组织僵硬的抑制。这些数据提示，CAF异质性的调节可能代表了PDAC治疗的一种策略。
Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.