Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, 210008, Nanjing, Jiangsu, China.
Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, 210008, Nanjing, China.
Nat Commun. 2022 Aug 31;13(1):5124. doi: 10.1038/s41467-022-32787-y.
The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC. WPOI 4-5-derived cancer-associated fibroblasts (CAFs), characterized by high oxytocin receptor expression (OXTR), contribute to local-regional metastasis. OXTR CAFs induce a desmoplastic stroma and CCL26 is required for the invasive phenotype of CCR3 tumors. Mechanistically, OXTR activates nuclear ERK5 transcription signaling via Gαq and CDC37 to maintain high levels of OXTR and CCL26. ERK5 ablation reprograms the pro-invasive phenotype of OXTR CAFs. Therefore, targeting ERK5 signaling in OXTR CAFs is a potential therapeutic strategy for OSCC patients with WPOI 4-5.
肿瘤细胞侵犯相邻正常组织的模式（POI）临床上可预测口腔鳞状细胞癌（OSCC）早期术后肿瘤转移/复发，但这些亚型发展的机制仍不清楚。我们关注每个肿瘤内 POI 最高评分（最差 POI，WPOI），观察到 WPOI 向高风险的 4/5 型驱动疾病进展的转变，与晚期 OSCC 中的间充质表型相关。WPOI 4-5 衍生的癌症相关成纤维细胞（CAFs），特征是高催产素受体表达（OXTR），有助于局部区域转移。OXTR CAFs 诱导纤维母细胞性基质形成，CCL26 是 CCR3 肿瘤侵袭表型所必需的。从机制上讲，OXTR 通过 Gαq 和 CDC37 激活核 ERK5 转录信号，以维持 OXTR 和 CCL26 的高水平。ERK5 消融使 OXTR CAFs 的促侵袭表型重新编程。因此，针对 OXTR CAFs 中的 ERK5 信号是 WPOI 4-5 的 OSCC 患者的一种潜在治疗策略。
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