胃癌（GC）的特点是对当前治疗药物具有强烈的抗药性，这归因于肿瘤起始和进展过程中高度异质性和未成熟表型的癌症干细胞（CSCs）。分泌性WNT2配体调节多个癌症通路，并已证明在胃肠道肿瘤中可能是一个潜在的治疗靶点；然而，其在胃癌CSCs（GCSCs）中的作用尚不清楚。在这里，我们发现WNT2的过表达增强了GCSCs的干性特性，促进了化疗耐药性和肿瘤形成能力。在机制上，WNT2受其转录因子SOX4的正调节，在此过程中，SOX4受经典WNT2/FZD8/β-连环蛋白信号通路的上调，形成一个自发调节性的正反馈循环，导致GCSCs自我更新和肿瘤形成能力的维持。此外，WNT2和SOX4同时过表达与临床GC标本中的预后较差以及对化疗的反应降低相关。使用特异性单克隆抗体阻断WNT2在GCSCs中显著干扰了WNT2-SOX4正反馈环路，并在GCSC衍生的小鼠异种移植模型中与化疗药物5-氟尿嘧啶和奥沙利铂协同应用时增强了化疗疗效。总的来说，本研究发现了一个新的WNT2-SOX4正反馈环路作为引发GCSCs耐药性的机制，并暗示WNT2-SOX4轴可能是胃癌治疗的潜在靶点。© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/β-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.