3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype.
3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype.
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早期黑色素瘤微环境的3D模型捕获巨噬细胞转化为肿瘤促进表型。
DOI：
10.3390/cancers13184579
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发表时间：
2021-09-12
期刊：
影响因子：
5.2
通讯作者：
Miller-Jensen K
中科院分区：
文献类型：
--
作者：
Pizzurro GA;Liu C;Bridges K;Alexander AF;Huang A;Baskaran JP;Ramseier J;Bosenberg MW;Mak M;Miller-Jensen K
我们开发了一个“肿瘤培养皿”实验系统来研究转移性黑色素瘤中有利于肿瘤生长和抑制免疫反应的早期事件。我们将小鼠黑色素瘤肿瘤细胞与成纤维细胞和巨噬细胞结合在3D胶原基质中，并表征了在肿瘤发生早期阶段存在的这三种细胞类型之间的相互作用如何驱动体内观察到的巨噬细胞的免疫抑制和促瘤转变。在共培养7天的过程中，我们量化了细胞间直接相互作用、细胞外基质和免疫介质分泌传递的信号动力学。我们发现巨噬细胞获得了与体内小鼠黑色素瘤肿瘤一致的特征和功能特征。该系统将为黑色素瘤微环境中巨噬细胞-基质串扰的未来研究提供支持，并为测试旨在刺激巨噬细胞免疫活性的潜在治疗方法提供平台。肿瘤的免疫反应是由肿瘤微环境（Tumor microenvironment， TME）塑造的，肿瘤微环境往往演变为免疫抑制，促进疾病的进展和转移。一个重要的例子是黑色素瘤，它显示出大量的肿瘤相关巨噬细胞（tam），这些巨噬细胞具有免疫抑制作用，但也具有恢复抗肿瘤活性的潜力。然而，为了治疗靶向tam，需要了解形成其肿瘤促进特征的早期事件。为了解决这个问题，我们构建并优化了三维体外共培养系统，该系统由胶原- i基质支架小鼠骨髓源性巨噬细胞（bmdm）， YUMM1.7黑色素瘤细胞和成纤维细胞组成，以重建早期黑色素瘤TME，并研究成纤维细胞和肿瘤细胞如何相互作用调节巨噬细胞的免疫活性。我们通过延时成像监测了BMDM的行为和相互作用，并描述了它们的激活和分泌。我们发现基质细胞诱导了快速的功能激活，BMDMs的运动性和反应增加。在7天的过程中，BMDMs获得了与已建立肿瘤中的黑色素瘤tam相似的表型和分泌谱。总之，在三维环境中，细胞与基质成分的直接相互作用使BMDM转变为类似tam的免疫抑制状态。我们的系统将使未来研究巨噬细胞间质串扰在黑色素瘤TME中的变化成为可能。
We developed a “tumor-in-a-dish” experimental system to study the early events favoring tumor growth and suppression of the immune response in metastatic melanoma. We combined murine melanoma tumor cells with fibroblasts and macrophages in a 3D collagen matrix and characterized how interactions between these three cell types, which are present in the early stages of tumorigenesis, drive immune suppression and the tumor-promoting transition in macrophages that is observed in vivo. Over the course of 7 days in the co-cultures, we quantified the dynamics of cues transmitted by direct cell–cell interactions, through the extracellular matrix and through secretion of immune mediators. We found that macrophages acquired features and a functional profile consistent with those present in in vivo murine melanoma tumors. This system will enable future studies of macrophage–stromal cross-talk in the melanoma microenvironment and provide a platform to test potential therapeutic approaches aimed at stimulating immune activity in macrophages. Tumor immune response is shaped by the tumor microenvironment (TME), which often evolves to be immunosuppressive, promoting disease progression and metastasis. An important example is melanoma tumors, which display high numbers of tumor-associated macrophages (TAMs) that are immunosuppressive but also have the potential to restore anti-tumor activity. However, to therapeutically target TAMs, there is a need to understand the early events that shape their tumor-promoting profile. To address this, we built and optimized 3D in vitro co-culture systems, composed of a collagen-I matrix scaffolding murine bone-marrow-derived macrophages (BMDMs), YUMM1.7 melanoma cells, and fibroblasts to recreate the early melanoma TME and study how interactions with fibroblasts and tumor cells modulate macrophage immune activity. We monitored BMDM behavior and interactions through time-lapse imaging and characterized their activation and secretion. We found that stromal cells induced a rapid functional activation, with increased motility and response from BMDMs. Over the course of seven days, BMDMs acquired a phenotype and secretion profile that resembled melanoma TAMs in established tumors. Overall, the direct cell–cell interactions with the stromal components in a 3D environment shape BMDM transition to a TAM-like immunosuppressive state. Our systems will enable future studies of changes in macrophage–stromal cross-talk in the melanoma TME.
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影响因子：
28.2
作者：
Kaur A;Ecker BL;Douglass SM;Kugel CH 3rd;Webster MR;Almeida FV;Somasundaram R;Hayden J;Ban E;Ahmadzadeh H;Franco-Barraza J;Shah N;Mellis IA;Keeney F;Kossenkov A;Tang HY;Yin X;Liu Q;Xu X;Fane M;Brafford P;Herlyn M;Speicher DW;Wargo JA;Tetzlaff MT;Haydu LE;Raj A;Shenoy V;Cukierman E;Weeraratna AT
通讯作者：
Weeraratna AT
影响因子：
41.2
作者：
Jain N;Vogel V
通讯作者：
Vogel V
影响因子：
8.8
作者：
Di Mitri, Diletta;Mirenda, Michela;Alimonti, Andrea
通讯作者：
Alimonti, Andrea
影响因子：
7.7
作者：
Barrett RL;Puré E
通讯作者：
Puré E
高维分析描述了成功的免疫检查癌症治疗过程中髓样和淋巴室的重塑。
影响因子：
64.5
作者：
Gubin MM;Esaulova E;Ward JP;Malkova ON;Runci D;Wong P;Noguchi T;Arthur CD;Meng W;Alspach E;Medrano RFV;Fronick C;Fehlings M;Newell EW;Fulton RS;Sheehan KCF;Oh ST;Schreiber RD;Artyomov MN
通讯作者：
Artyomov MN