CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment.
CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment.
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CREB3L1通过重塑肿瘤微环境促进甲状腺未分化癌肿瘤生长和转移
DOI：
10.1186/s12943-022-01658-x
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发表时间：
2022-10-03
期刊：
影响因子：
37.3
通讯作者：
Ge M
中科院分区：
文献类型：
--
作者：
Pan Z;Xu T;Bao L;Hu X;Jin T;Chen J;Chen J;Qian Y;Lu X;Li L;Zheng G;Zhang Y;Zou X;Song F;Zheng C;Jiang L;Wang J;Tan Z;Huang P;Ge M
甲状腺间变性癌（ATC）是一种极恶性的内分泌癌，常伴有甲状腺外扩展或转移，其机制尚不清楚。我们在一个由四个微阵列数据集组成的大型队列中筛选了CREB3转录因子家族。这表明CREB3L1在ATC组织中特异性上调，并与甲状腺癌患者的总生存率呈负相关。在一项独立的队列研究中，CREB3L1的高表达与无进展生存期一致呈负相关。CREB3L1敲低可显著减弱ATC细胞的侵袭，而CREB3L1过表达可促进甲状腺乳头状癌（PTC）细胞的侵袭。在斑马鱼和裸鼠模型中，CREB3L1的缺失抑制ATC异种移植瘤的转移和肿瘤生长。单细胞rna测序分析显示，在甲状腺滤泡上皮细胞向ATC细胞的肿瘤进展过程中，CREB3L1的表达逐渐增加，并伴有细胞外基质（ECM）信号的激活。CREB3L1敲低可显著降低ATC细胞中胶原亚型的表达和异种移植物中原纤维胶原的表达。由于CREB3L1的缺失，ATC细胞无法激活α-平滑肌肌动蛋白（α-SMA）阳性的癌症相关成纤维细胞（CAFs）。CREB3L1敲低后，cas的存在抑制了ATC球体的生长和ATC细胞的转移。进一步的细胞因子阵列筛选表明，ATC细胞通过creb3l1介导的IL-1α产生激活α- sma阳性的CAFs。此外，KPNA2介导CREB3L1的核易位，从而激活下游ECM信号。这些结果表明，CREB3L1通过激活ECM信号，维持ATC细胞的ca样特性，重塑肿瘤间质微环境，驱动ATC的恶性化。图形抽象
Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC.Graphical Abstract
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DOI：
10.1038/s41571-021-00546-5
发表时间：
2021-12
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Chen Y;McAndrews KM;Kalluri R
通讯作者：
Kalluri R
影响因子：
4
作者：
Garcia, Iris A.;Torres Demichelis, Vanina;Alvarez, Cecilia
通讯作者：
Alvarez, Cecilia
影响因子：
6.6
作者：
Hoffmann, S;Maschuw, K;Zielke, A
通讯作者：
Zielke, A
影响因子：
6.4
作者：
Dahlman, T;Lammerts, E;Rubin, K
通讯作者：
Rubin, K
影响因子：
46.9
作者：
Gao R;Bai S;Henderson YC;Lin Y;Schalck A;Yan Y;Kumar T;Hu M;Sei E;Davis A;Wang F;Shaitelman SF;Wang JR;Chen K;Moulder S;Lai SY;Navin NE
通讯作者：
Navin NE