Sp1调控的炎性介质诱导巨噬细胞M2极化介导胰腺癌耐药的机制

胰腺癌的化疗耐药是临床治疗效果不佳的关键原因。越来越多的证据表明，胰腺癌微环境中M2型巨噬细胞与肿瘤细胞的交互作用，在介导化疗耐药过程中扮演着重要的角色，但具体的分子机制不清楚。课题组前期研究证实，高表达转录因子Sp1的胰腺癌细胞可通过调控炎性介质的分泌，诱导巨噬细胞向M2表型极化；进一步研究发现，极化的M2型巨噬细胞又可通过分泌炎性介质，激活肿瘤细胞中EGFR/P38/MAPK信号通路，上调Sp1表达，从而形成正反馈环路；该反馈环路通过上调肿瘤细胞干性特征，介导化疗耐药。本课题将在前期研究基础上，从临床病例着手，结合分子、细胞生物学以及模式动物水平，围绕“Sp1-M2型巨噬细胞-化疗耐药”这一主线，从多层次、多角度研究“Sp1-炎性介质-M2型巨噬细胞-炎性介质-Sp1”正反馈环路，阐明胰腺癌临床化疗耐药可能的分子机制，进而为逆转化疗耐药策略的制定以及挖掘新的潜在治疗靶点提供依据。

Chemoresistance is a critical factor for poor clinical outcomes in pancreatic cancer. Several investigations suggest that reciprocal interaction of M2 macrophages and tumor cells in pancreatic microenvironment play an important role in mediating chemoresistance, but the underlying mechanisms remain unclear. Our group previously revealed that high expression of the transcription factor Sp1 in pancreatic cancer cells induced macrophage polarization to the M2 phenotype by regulating the secretion of inflammatory mediators. Further studies indicate that inflammatory mediators secreted by M2-like macrophages might up-regulate Sp1 expression through activation of tumor cell EGFR / P38 / MAPK signaling pathway. These form a positive feedback loop, which mediate chemoresistance through upregulation of stemness. Based on our previous work, we would like to elucidate the hypothesis, “Sp1-M2 macrophages-chemoresistance”, from the molecular, cellular and animal models to clarify "Sp1-inflammatory mediators-M2 macrophages-inflammatory mediators-Sp1" positive feedback loop from different perspectives, with an aim to investigate the possible mechanisms of chemoresistance and provide scientific basis into reversal of chemoresistance strategy modulation and uncover potential therapeutic targets in pancreatic cancer.