Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.
Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.
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DOI：
10.1038/s41388-022-02493-6
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发表时间：
2022-11
期刊：
影响因子：
8
通讯作者：
Batra SK
中科院分区：
文献类型：
--
作者：
Lakshmanan I;Marimuthu S;Chaudhary S;Seshacharyulu P;Rachagani S;Muniyan S;Chirravuri-Venkata R;Atri P;Rauth S;Nimmakayala RK;Siddiqui JA;Gautam SK;Shah A;Natarajan G;Parte S;Bhyravbhatla N;Mallya K;Haridas D;Talmon GA;Smith LM;Kumar S;Ganti AK;Jain M;Ponnusamy MP;Batra SK
MUC16，膜结合粘蛋白，在胰腺导管腺癌（PDAC）中起致癌作用。然而，MUC16与KrasG12D和Trp53R172H突变合作，在PDAC进展、肿瘤微环境和转移中的病理作用尚不清楚。在小鼠中，缺失带有KrasG12D/+和Trp53R172H/+激活突变的Muc16可显著降低KrasG12D/+的进展并延长总生存期；Trp53R172H / +;Pdx-1-Cre;Muc16−/−(KPCM)和KrasG12D/+；Pdx-1-Cre;Muc16−/−(KCM)，与KrasG12D/+相比；Trp53R172H / +;Pdx-1-Cre （KPC）与KrasG12D/+；Pdx-1-Cre （KC）小鼠。Muc16基因敲除胰腺肿瘤（KPCM）与KPC相比，肿瘤微环境因子减少，肝和肺转移发生率显著降低。此外，计算机数据分析显示MUC16与活化的基质和转移相关基因呈正相关。KPCM小鼠同基因细胞的转移能力和内皮细胞结合能力明显低于KPC细胞。同样，KPCM类器官的生长速率明显低于KPC类器官。有趣的是，RNA-seq数据显示，细胞骨架蛋白Actg2、Myh11和Pdlim3在KPCM肿瘤中下调。进一步敲除这些基因显示转移潜力降低。总之，我们的研究结果表明，Muc16通过改变Actg2、Myh11和Pdlim3基因的表达来改变胰腺癌进展和转移过程中的肿瘤微环境因素。
MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with KrasG12D and Trp53R172H mutations remains unknown. Deletion of Muc16 with activating mutations KrasG12D/+ and Trp53R172H/+ in mice significantly decreased progression and prolonged overall survival in KrasG12D/+; Trp53R172H/+; Pdx-1-Cre; Muc16−/− (KPCM) and KrasG12D/+; Pdx-1-Cre; Muc16−/− (KCM), as compared to KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) and KrasG12D/+; Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis- associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate than KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.
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影响因子：
4.8
作者：
Chen, Shih-Hsun;Dallas, Matthew R.;Konstantopoulos, Konstantinos
通讯作者：
Konstantopoulos, Konstantinos
影响因子：
--
作者：
Das S;Rachagani S;Torres-Gonzalez MP;Lakshmanan I;Majhi PD;Smith LM;Wagner KU;Batra SK
通讯作者：
Batra SK
影响因子：
37.3
作者：
Felder M;Kapur A;Gonzalez-Bosquet J;Horibata S;Heintz J;Albrecht R;Fass L;Kaur J;Hu K;Shojaei H;Whelan RJ;Patankar MS
通讯作者：
Patankar MS
影响因子：
4.6
作者：
Chen SH;Hung WC;Wang P;Paul C;Konstantopoulos K
通讯作者：
Konstantopoulos K
影响因子：
3.5
作者：
Caffrey, Thomas;Sagar, Satish;Radhakrishnan, Prakash
通讯作者：
Radhakrishnan, Prakash