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.

锯齿状息肉病综合征 (SPS) 表现为大肠内多发无蒂锯齿状病变 (SSL)，并导致结直肠癌 (CRC) 风险增加。然而，SPS 的病因尚不清楚。 SSL 衍生的类器官此前尚未被研究过，但可能有助于深入了解 SPS 发病机制并确定新的生物标志物和化学预防策略。本研究探讨了 SPS 患者未受累结肠和息肉来源的类器官培养物中 EGFR 和 COX 通路抑制的影响。我们还与代表遗传性胃肠道综合征、家族性腺瘤性息肉病（FAP）和林奇综合征（LS）的类器官进行了比较。从 SPS、FAP、LS 和非综合征筛查结肠镜检查患者的未受累结肠和息肉中产生 18 个总类器官结肠培养物。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）单独或联合应用。使用 44 个靶基因定制 mRNA 组（包括 WNT 和 COX 途径基因）和 798 个基因的 microRNA 基因组，通过 NanoString 分析定量类器官 RNA 表达。厄洛替尼治疗显着降低了所有四类患者未受累结肠以及所有 SSL 和腺瘤性息肉的类器官中与 WNT 和 MAPK 激酶信号传导相关的 mRNA 水平。舒林酸不会改变任何培养物中的 mRNA 谱。我们的研究结果表明 EGFR 抑制剂可能有助于 SSL 的化学预防治疗。这些发现也可能有助于在 SPS 患者中使用这些药物的临床试验设计。我们的研究中鉴定出的差异表达基因（MYC、FOSL1、EGR1、IL33、LGR5 和 FOXQ1）可用于鉴定 SSL 化学预防的其他新分子靶点。