Transcriptome Analysis of Human Pancreatic Stellate Cells Co-cultured With PAK1-Modulated Cells Revealed the Role of Cytokine Pathway in Tumor Microenvironment.

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high metastatic ability, poor prognosis, and resistant to treatment. Tumor microenvironment plays a major role in the complexity of PDAC.

OBJECTIVE OF THE STUDY: The aim of the study was to examine the role of P21 activated kinase-1 (PAK1) in the sustenance of tumor microenvironment to enable tumor growth and progression.

METHODOLOGY: The effect of PAK1 in the tumor microenvironment was analyzed using a novel co-culture method involving pancreatic cancer cells and pancreatic stellate cells. The 2 cell types were grown in both direct and indirect cell culture models to facilitate the juxtracrine signaling and establish a secretome network. The established network was studied using the transcriptome sequencing of PAK1-modulated MIA PaCa-2 cells co-cultured with stellate cells.

RESULTS

The results showed that PAK1 influenced cells have increased interferon pathway when compared to PAK1 depleted cells. The levels of chemokine CCL3 was altered in PAK1-modulated cells as evidenced by the bioinformatic, QPCR, and ELISA analysis. The pathway and interactome analysis showed that CCL3 promotes interferon activation and myofibroblast differentiation in pancreatic cancer microenvironment. These results might help in identifying the PAK1 induced metastatic network in pancreatic cancer. Further investigation will provide adequate evidence of CCL3 and PAK1 in pancreatic carcinogenesis and metastasis.

CONCLUSIONS

The present study provides an understanding of tumor microenvironment and involvement of inflammatory cytokines in a juxtacrine mechanism to aggravate and accelerate pancreatic adenocarcinoma.