PO.TB10.03 · 肿瘤生物学
由应激信号调控的III型胶原通过诱导肿瘤休眠和重塑免疫抑制性生态位驱动胰腺癌化疗抵抗
Type III collagen regulated by stress signaling drives chemoresistance in pancreatic cancer by inducing tumor dormancy and remodeling the immunosuppressive niche
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摘要 Abstract
中文摘要
化疗抵抗仍然是胰腺导管腺癌（PDAC）治疗失败的主要原因。治疗诱导的肿瘤休眠使肿瘤细胞得以逃避化疗的细胞毒性。我们的研究揭示，吉西他滨（gemcitabine）治疗触发细胞外基质（ECM）纤维化和胶原重排，伴随III型胶原（COL3）的显著积累。关键的是，在皮下和原位PDAC模型中外源性补充COL3能够诱导肿瘤细胞休眠，伴随p21/p27上调，并促进化疗抵抗。同时，COL3在化疗抵抗性生态位内富集肿瘤相关巨噬细胞（TAM）。机制上，COL3的诱导由化疗应激期间CREB3L1激活的未折叠蛋白反应（UPR）驱动。CREB3L1调控休眠相关分子如COL3、p21和p27，并重塑基质微环境。这些发现确立了COL3作为PDAC化疗抵抗的核心介质，通过协调休眠和免疫抑制性生态位的形成发挥作用。靶向CREB3L1-COL3轴是克服胰腺癌获得性抵抗的一个有前景的策略。
查看英文原文 English abstract
Chemotherapy resistance remains the primary cause of treatment failure in pancreatic ductal adenocarcinoma (PDAC). Therapy induced tumor dormancy enables tumor cells escape from chemotherapy cytotoxicity. Our study reveals that gemcitabine treatment triggers extracellular matrix (ECM) fibrosis and collagen rearrangement, with significant accumulation of type III Collagen (COL3). Crucially, exogenous COL3 supplementation in subcutaneous and orthotopic PDAC models could induce tumor cell dormancy accompanied by p21/p27 upregulation and promote chemoresistance. Meanwhile, COL3 enrich tumor-associated macrophages (TAMs) within chemoresistant niches. Mechanistically, COL3 induction was driven by CREB3L1-activated unfolded protein response (UPR) during chemotherapy stress. CREB3L1 regulated dormancy associated molecules like COL3, p21 and p27 and remodeled the stromal microenvironment. These findings establish COL3 as a central mediator of PDAC chemoresistance by orchestrating dormancy and immunosuppressive niche formation. Targeting the CREB3L1-COL3 axis represents a promising strategy to overcome acquired resistance in pancreatic cancer.
利益披露 Disclosure
H. Xu, None..
Y. Zhou, None..
S. Xue, None..
S. Wu, None..
L. Wang, None.