Abstract：
Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.
摘要：
锯齿状息肉病综合征（SPS）表现为大肠中多个无柄锯齿状病变（SSL），并增加了结直肠癌（CRC）的风险。然而,SPS的病因尚不清楚。SSL衍生的类器官以前尚未研究过，但可能有助于提供对SPS发病机理的见解，并确定新的生物标志物和化学预防策略。这项研究检查了EGFR和COX途径抑制在源自SPS患者未受累的结肠和息肉的类器官培养物中的作用。我们还与代表遗传性胃肠道综合征的类器官进行了比较，家族性腺瘤性息肉病（FAP）和林奇综合征（LS）。SPS中未受累的结肠和息肉产生了18个总的类器官结肠培养物，FAP,LS,和非综合征筛查结肠镜检查患者。确定每种培养物的BRAF和KRAS突变状态。厄洛替尼(EGFR抑制剂)和舒林酸(COX抑制剂)单独应用和组合应用。使用44靶基因定制mRNA组(包括WNT和COX途径基因)和798基因microRNA基因组通过NanoString分析定量类器官RNA表达。厄洛替尼治疗显著降低了来自所有四种患者类别以及来自所有SSL和腺瘤性息肉的未受累结肠的类器官中与WNT和MAPK激酶信号传导相关的mRNA水平。舒林酸在任何培养物中都没有改变mRNA谱。我们的研究结果表明，EGFR抑制剂可能有助于SSLs的化学预防治疗。这些发现还可以促进在SPS患者中使用这些药物的临床试验设计。在我们的研究中鉴定的差异表达基因(MYC，FOSL1，EGR1，IL33，LGR5和FOXQ1）可用于鉴定用于化学预防SSL的其他新分子靶标。
