钠葡萄糖共转运载体SGLT1重塑免疫抑制微环境促进乳腺癌内分泌治疗耐药的分子机制研究

Endocrine therapy resistance is the leading cause of disease progression and death in estrogen receptor positive breast cancer patients, and overcoming endocrine therapy resistance remains to be the overarching challenge in the field of breast cancer. Tumor metabolic reprogramming initiated microenvironmental immunological rebuilding is recognized to play an important role in cancer progression, but its relationship with breast cancer endocrine resistance is not clear. Our previous studies have found that there is a close relationship between sodium/glucose co-transporter 1 (SGLT1) upregulation and repression of immune cells within the tumor microenvironment in the progression of endocrine resistance, and inhibition of SGLT1 prohibited endocrine resistance, suggesting that SLGT1 dependent glucose uptake and metabolic alteration plays an important role in regulating microenvironmental immunity and endocrine sensitivity. The aim of this study is to determine the key factors and main pathways that mediate the SGLT1 based metabolic reprogramming and microenvironmental immunosuppression by using drug-resistant cell lines, animal models and human endocrine-resistant tumor tissue specimens. This study will reveal the complex network and key nodes sustaining the interplay of metabolic remodeling and immune repression within tumor microenvironment, and it will illustrate the mechanism underlying microenvironmental immune suppression promoted endocrine drug resistance of breast cancer. The originality of this study stems from an innovative perspective of combining cancer energy metabolism and immunity of tumor microenvironment. The outcomes of this study will provide a novel theoretical foundation and new treatment approaches to reverse endocrine therapy resistance of breast cancer.

内分泌治疗耐药是限制雌激素受体阳性乳腺癌临床疗效的主要原因，是乳腺癌研究领域亟待解决的重要问题。代谢重塑及微环境改变在肿瘤发生发展中的调控作用越来越受关注，但其与乳腺癌内分泌耐药是否相关尚不清楚。本课题组前期结果发现钠葡萄糖共转运载体（SGLT1）在内分泌耐药患者组织中表达增加，干预其表达明显抑制耐药表型；耐药肿瘤微环境中M2型TAM比例增加，TILs受损明显；耐药细胞和患者肿瘤组织中自噬发生增加。本项目拟从细胞、动物、临床标本水平，利用分子生物学、代谢组学、免疫学等多种研究方法，重点研究SGLT1介导的代谢重塑作用及其诱导的免疫抑制微环境调控内分泌治疗耐药的分子机制，从代谢对于免疫微环境影响的角度入手，揭示肿瘤代谢及免疫抑制微环境促进内分泌耐药的分子调控网络。本研究有助于从根本上揭示内分泌治疗耐药机制，为临床预防和逆转乳腺癌内分泌治疗耐药提供理论依据和药物作用靶点。

内分泌治疗耐药是限制雌激素受体阳性乳腺癌临床疗效的主要原因，是乳腺癌研究领域亟待解决的重要问题。代谢重塑及微环境改变在肿瘤发生发展中的调控作用越来越受关注，但其与乳腺癌内分泌耐药是否相关尚不清楚。本课题组在前期研究的基础上，鉴定了耐药乳腺癌细胞代谢与自噬特征，证实SGLT1在乳腺耐药肿瘤中过表达，与乳腺癌内分泌治疗耐药密切相关；通过体内外研究明确了SGLT1介导的肿瘤细胞糖代谢增强可导致乳酸生成增多，通过HIF-1α /STAT3途径调节M2样巨噬细胞极化；M2样巨噬细胞可分泌EGF等生长因子，促进乳腺癌细胞PI3K/Akt信号通路激活，进而调节SGLT1的表达，形成耐药乳腺癌细胞代谢和M2样巨噬细胞极化之间的反馈调节通路；应用代谢抑制剂有望克服或改善肿瘤治疗耐药。本研究有助于从根本上揭示内分泌治疗耐药机制，为临床预防和逆转乳腺癌内分泌治疗耐药提供理论依据和药物作用靶点。