Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma

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 Kras(G12D) and Trp53(R172H) mutations remains unknown. Deletion of Muc16 with activating mutations Kras(G12D/+) and Trp53(R172H/+) in mice significantly decreased progression and prolonged overall survival in Kras(G12D/+); Trp53(R172H/+); Pdx-1-Cre; Muc16(-/-) (KPCM) and Kras(G12D/+); Pdx-1-Cre; Muc16(-/-) (KCM), as compared to Kras(G12D/+); Trp53(R172H/+); Pdx-1-Cre (KPC) and Kras(G12D/+); 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 compared to 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.

Automated summary

Muc16 plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). Deletion of Muc16 can decrease tumor progression and improve overall survival in mice models. Muc16 knockout reduces tumor microenvironment factors and incidence of liver and lung metastasis. Further research shows that Muc16 alters the expression of Actg2, Myh11, and Pdlim3 genes, affecting pancreatic cancer progression and metastasis.