OXTR+DUSP4-肿瘤相关成纤维细胞在口腔鳞癌浸润中的作用机制研究

Oral squamous cell carcinoma (OSCC) pathologically show different pattern of invasion, which contributes to the development of OSCC. Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment and contain different subpopulations with distinct phenotypes and functions, which are critically involved in the whole cancer progression, but the correlations between CAFs heterogeneity and pattern of invasion in OSCC remain to be further elucidated. We previously found that OSCC patients with poor pattern of invasion showed high incidence of locoregional recurrence and lymph node metastasis. Using high-throughput sequencing, we identified a unique CAF subset which was positive for OXTR but negative for DUSP4 in OSCC tissues with poor pattern of invasion, namely OXTR+DUSP4- CAFs. Function analysis indicated that OXTR+DUSP4- CAFs was characteristic of aberrant activated MAPK pathway, high proliferation rate and producing more tumor invasion-related IL-6 and TGF-β. Therefore, we speculated that activated MAPK pathway in OXTR+DUSP4- CAFs contributed to the maintenance of high proliferation rate and, meanwhile, producing abundant IL-6 and TGF-β to induce tumor invasion and form the poor pattern of invasion. In this study, we aimed to define this CAF subset though determining the correlation between OXTR+DUSP4- CAFs and locoregional recurrence and lymph node metastasis in OSCC patients, and investigating the mechanisms of this CAF subset involving in its proliferation and the function of promoting tumor invasion in vitro and in vivo, which was conducive to overcoming CAF-supported tumor microenvironment.

口腔鳞癌（OSCC）在入侵正常组织过程中具有不同浸润方式（POI），与肿瘤恶性程度密切相关。已知肿瘤相关成纤维细胞（CAFs）具有异质性，参与调控肿瘤细胞的多种行为，但它与浸润方式的关系尚不清楚。我们前期研究发现，具有较差浸润方式的OSCC患者转移和复发率较高，且此类OSCC中存在一群独特表型的CAFs亚群：OXTR+DUSP4-CAFs，其增殖能力强并高表达促肿瘤浸润因子IL-6和TGF-β。此外，OXTR+DUSP4-表型与持续活化的MAPK信号通路密切相关。故推测，高度增殖的OXTR+DUSP4-CAFs可能通过MAPK信号的持续活化促进IL-6和TGF-β依赖的OSCC浸润，诱导较差浸润方式。本项目拟分析该CAF亚型与OSCC复发及转移的关系，通过细胞模型和动物模型探索OXTR+DUSP4-CAFs维持自身增殖以促进OSCC浸润的机制，为克服CAFs依赖的肿瘤微环境提供新思路。

口腔鳞癌（OSCC）在入侵正常组织过程中具有不同浸润方式（POI），与肿瘤恶性程度密切相关。已知肿瘤相关成纤维细胞（CAFs）具有异质性，参与调控肿瘤细胞的多种行为，但它与浸润方式的关系尚不清楚。本研究证实OSCC患者存在5种浸润类型，主要分为低浸润型WPOI 1-3和高浸润型WPOI 4-5，晚期OSCC患者更易表现为WPOI 4-5型，且生存时间较短，是OSCC独立的预后因素。且WPOI 4-5患者具有更多肿瘤相关成纤维细胞，相比于CAF WPOI 1-3，CAF WPOI 4-5能够促进间质胶原的产生，促进肿瘤细胞的局部浸润和淋巴结转移。高表达OXTR的CAFs是WPOI 4-5肿瘤间质的重要标志，敲除OXTR能够抑制 WPOI 4-5来源CAF的促浸润功能，后续研究证实CCL26是OXTR+CAF促进肿瘤浸润的重要调控因素，OXTR能够活化ERK5激酶，促进CCL26转录。靶向OXTR阳性的CAF能够抑制肿瘤浸润的能力，从而克服CAF依赖的抑制性肿瘤微环境。