The Wenner-Gren Institute, Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Front Immunol. 2023 Sep 19;14:1243797. doi: 10.3389/fimmu.2023.1243797. eCollection 2023.
Tumor-associated macrophages may act to either limit or promote tumor growth, yet the molecular basis for either path is poorly characterized.
We use a larval model that expresses a dominant-active version of the Ras-oncogene (Ras) to study dysplastic growth during early tumor progression. We performed single-cell RNA-sequencing of macrophage-like hemocytes to characterize these cells in tumor- compared to wild-type larvae. Hemocytes included manually extracted tumor-associated- and circulating cells.
We identified five distinct hemocyte clusters. In addition to Ras larvae, we included a tumor model where the activation of effector caspases was inhibited, mimicking an apoptosis-resistant setting. Circulating hemocytes from both tumor models differ qualitatively from control wild-type cells-they display an enrichment for genes involved in cell division, which was confirmed using proliferation assays. Split analysis of the tumor models further reveals that proliferation is strongest in the caspase-deficient setting. Similarly, depending on the tumor model, hemocytes that attach to tumors activate different sets of immune effectors-antimicrobial peptides dominate the response against the tumor alone, while caspase inhibition induces a shift toward members of proteolytic cascades. Finally, we provide evidence for transcript transfer between hemocytes and possibly other tissues. Taken together, our data support the usefulness of to study the response against tumors at the organismic level.
肿瘤相关巨噬细胞可能会限制或促进肿瘤生长，但这两种途径的分子基础仍未得到很好的描述。
我们使用一种表达显性激活形式 Ras 癌基因的幼虫模型来研究早期肿瘤进展过程中的发育不良生长。我们对类似于巨噬细胞的血淋巴细胞进行了单细胞 RNA 测序，以在肿瘤与野生型幼虫相比时对这些细胞进行特征描述。血淋巴细胞包括手动提取的肿瘤相关细胞和循环细胞。
我们鉴定了五个不同的血淋巴细胞簇。除了 Ras 幼虫外，我们还包括了一种抑制效应半胱天冬酶激活的肿瘤模型，模拟了一种抗细胞凋亡的环境。来自两种肿瘤模型的循环血淋巴细胞在性质上与对照野生型细胞不同——它们显示出参与细胞分裂的基因富集，这通过增殖测定得到了证实。肿瘤模型的分裂分析进一步表明，在缺乏半胱天冬酶的环境中增殖最强。同样，根据肿瘤模型的不同，附着在肿瘤上的血淋巴细胞会激活不同的免疫效应物集——单独针对肿瘤时，抗菌肽占主导地位，而半胱天冬酶抑制诱导蛋白酶级联反应的成员发生转变。最后，我们提供了血淋巴细胞与可能其他组织之间转录转移的证据。综上所述，我们的数据支持使用该模型在机体水平上研究针对肿瘤的反应。
