Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable model for investigating systemic sclerosis-related pathologies due to increased extracellular matrix deposition, fibrosis in connective tissues, and altered immune cell activation. Despite the role of extracellular matrix and fibrosis in cancer progression, the potential of the TSK mouse as a model for cancer studies is unexplored.Methods:To investigate the impact of the altered microenvironment in TSK mice on cancer progression, we compared the tumor-forming capabilities (by subcutaneous and intraperitoneal injection) in TSK mice and WT mice using syngeneic breast cancer, melanoma, and ovarian cancer cell lines. We used bulk and single-cell RNA sequencing to characterize these tumors and identify the changes in the TSK microenvironment that promote cancer formation.Results:In all three cancer types, TSK mice exhibited more invasive subcutaneous tumors in comparison to WT controls, underscoring the role of the TSK subcutaneous microenvironment in promoting cancer progression. Furthermore, the heightened invasiveness of ovarian tumors implanted intraperitoneally suggests that the peritoneal microenvironment in TSK mice also promotes tumor progression. Single-cell RNA sequencing analyses of subcutaneous tumors from TSK and WT mice revealed tumor-specific changes in the composition and phenotype of various cell populations. The most consistent alteration in TSK mice included a higher neutrophil-to-lymphocyte ratio and an enrichment in profibrotic subpopulations of myofibroblasts and macrophages.Conclusions:Our research unveils the TSK mouse as a valuable model for studying the intricate connections between systemic sclerosis and cancer
背景：系统性硬化症患者在发病后几年内发生各种实体恶性肿瘤的风险显著增加，但其促进肿瘤发生的机制尚不明确。由于细胞外基质沉积增加、结缔组织纤维化及免疫细胞活化改变，紧皮（TSK）小鼠已成为研究系统性硬化症相关病理的重要模型。尽管细胞外基质和纤维化在癌症进展中发挥作用，但TSK小鼠作为癌症研究模型的潜力尚未被探索。 方法：为探究TSK小鼠微环境改变对癌症进展的影响，我们采用同基因乳腺癌、黑色素瘤和卵巢癌细胞系，通过皮下及腹腔注射方式比较TSK小鼠与野生型（WT）小鼠的成瘤能力。通过批量及单细胞RNA测序技术对这些肿瘤进行表征，以明确TSK微环境中促进癌症形成的关键变化。 结果：在所有三种癌症类型中，与WT对照组相比，TSK小鼠均表现出更具侵袭性的皮下肿瘤，这凸显了TSK皮下微环境在促进癌症进展中的作用。此外，腹腔植入的卵巢肿瘤侵袭性增强表明，TSK小鼠的腹膜微环境同样促进肿瘤进展。对TSK和WT小鼠皮下肿瘤的单细胞RNA测序分析显示，各类细胞群在组成和表型上存在肿瘤特异性变化。TSK小鼠中最一致的变化包括更高的中性粒细胞与淋巴细胞比率，以及促纤维化亚群的肌成纤维细胞和巨噬细胞富集。 结论：本研究揭示了TSK小鼠可作为研究系统性硬化症与癌症之间复杂关联的重要模型。
Cancer Growth and Invasion Are Increased in the Tight Skin (TSK) Mouse
肿瘤(癌症)患者之家