First Key Step in the Formation of Pancreatic Cancer Identified

Researchers from Mayo Clinic have found the first step of the origin of Pancreatic Cancer. Their new finding demonstrates new clues for the tactics of pancreatic cancer prevention. This study was published in Cancer Discovery.

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Oncogenic KRAS mutations drive metaplasia of pancreatic acinar cells to a highly proliferative duct-like cell type, which is the precursor for precancerous pancreatic intraepithelial neoplastic (PanIN) lesions. Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions.

In this study, researchers report that oncogenic KRAS mutations in pancreatic acinar cells induce the expression of intercellular adhesion molecule-1(ICAM-1). They show that ICAM-1 can act as a chemoattractant for macrophages. Attracated macrophages release matrix-degrading enzymes, including matrix metalloproteinase 9(MMP9), as well as cytokines such as TNF that synergize with KRAS mutations to drive acinar cell metaplasia. They also demonstrate that depleting marcrophages or neutralizing ICAM-1 in p48Cre, KrasG12D-expressing mice dampens the development of precancerous lesions.

In summary, this study for the first time demonstrate that KrasG12D-expressing acinar cells can expedite their transformation to a duct-like phenotype by inducing local inflammation and macrophage infiltration. They provide a mechanism of how oncogenic Kras mutations and inflammatory microenvironment function synergistically to drive the earliest abnormal pancreatic structures that precede PDA.

Reference:

Liou G Y, Doppler H, Necela B, et al. Mutant Kras-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions[J]. Cancer discovery, 2014: CD-14-0474.

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