Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

Disruption of skin homeostasis by environmental insults activates pathologic circuitries leading to inflammation and carcinogenesis. Galectin-7 (Gal-7), a lectin preferentially expressed in keratinocytes, has been implicated in wound healing and defective skin repair. Here we report using genetically-engineered mouse models and human samples, essential roles for Gal-7 during skin carcinogenesis via coordinated intracellular and extracellular mechanisms. Heightened Gal-7 expression delineated malignant lesions in non-melanoma skin cancer (NMSC) patients and shaped the course of skin carcinogenesis in mice. Intracellularly, increased Gal-7 conferred genomic instability to skin lesions and favored transcription of inflammation-related genes reprogramming the immune landscape toward a myeloid immunoregulatory profile. Extracellularly, Gal-7 accelerated skin carcinogenesis through glycan-dependent induction of monocytic myeloid-derived suppressor cells with enhanced immune regulatory activity. Our findings identify a lectin-driven molecular circuitry that promotes skin carcinogenesis by coupling genomic instability, transcriptional regulation and myeloid immunosuppressive programs, suggesting a potential therapeutic target for the treatment of NMSC. Trasncriptomic analysis of skin papillomas derived from the two-stage carcinogenesis model (DMBA/TPA) in wild-type (WT), Lgals7-/- (KO) and Tg46 transgenic mice constitutively expressing Gal-7 under the Keratin-14 promoter.

环境刺激破坏皮肤稳态（skin homeostasis）后，会激活病理信号通路，进而引发炎症反应与癌变进程。半乳糖凝集素7（Galectin-7，Gal-7）是一类优先在角质形成细胞中表达的凝集素（lectin），既往研究已证实其参与伤口愈合与皮肤修复缺陷的病理过程。本研究借助基因工程小鼠模型与人类临床样本，揭示了Gal-7在皮肤癌变过程中的核心调控作用，其机制涉及胞内与胞外的协同调控通路。在非黑色素瘤皮肤癌（non-melanoma skin cancer, NMSC）患者体内，Gal-7表达水平升高可作为恶性病变的标志性特征，同时该分子可调控小鼠皮肤癌变的病程进展。胞内层面，Gal-7表达上调会诱导皮肤病变产生基因组不稳定性（genomic instability），并促进炎症相关基因的转录，重塑肿瘤免疫微环境，使其偏向髓系免疫调节表型。胞外层面，Gal-7通过聚糖依赖（glycan-dependent）的信号通路，诱导单核细胞系髓系来源抑制细胞（monocytic myeloid-derived suppressor cells）并增强其免疫调节活性，从而加速皮肤癌变的发生发展。本研究发现了一条由凝集素介导的分子调控环路，该环路通过耦合基因组不稳定性、转录调控程序与髓系免疫抑制通路，促进皮肤癌变，提示Gal-7可作为非黑色素瘤皮肤癌治疗的潜在靶点。本研究针对野生型（wild-type, WT）、Lgals7基因敲除（Lgals7-/-，KO）以及在角蛋白14（Keratin-14）启动子调控下组成型表达Gal-7的Tg46转基因小鼠，采用二阶段癌变模型（DMBA/TPA）构建的皮肤乳头状瘤（skin papillomas）样本，开展了转录组学（transcriptomic）分析。