Role of p21-activated kinase in Tumorigenesis and Inflammation

Increased expression and kinase activity of p21-activated kinases (PAKs) is a prominent driver of oncogenesis. These serine-threonine kinases have been identified as promising targets for cancer therapy although no safe and specific inhibitors have been successfully developed yet. The isoforms PAK1 and PAK2 modulate critical signaling pathways including cell proliferation, inflammatory responses, cytoskeleton reorganization, and gene expression. However, their specific biological functions and potential redundancy in the myeloid compartment are poorly described in vivo. Therefore, we generated PAK1/2 deficient mice by combining global PAK1 (Pak1-/-) and myeloid-specific PAK2 (mPak2-/-) deletion strains. PAK1/2 combined deletion triggered spontaneous development of disseminated hemophagocytic histiocytic sarcoma (HHS) in mice, a rare aggressive myeloid neoplasm of macrophage origin, with a poor prognosis and no specific treatment in humans and susceptible dog breeds. Both PAK1 and PAK2 contributed to the establishment of the malignancy as HS never occured in single PAK1 or PAK2 deficient mice. In our study, PAK1 and PAK2 appeared to be crucial regulators of cytoskeleton dynamics, cell cycle, phagocytosis, an innate immune checkpoint, and oxidative/nitrosative stress in myeloid cells, but also in intestinal barrier function. Thus, the tumor suppressive role of PAKs in HHS raises concerns about developing and using of poorly specific PAK inhibitors in cancer therapy. Overall, PAK1/2 deficient mice represent a promising model for preclinical studies of early histiocytic sarcoma development but also for the investigation of cytoskeleton and chronic inflammation dynamics in tumorigenesis and the overall regulatory functions of PAK1/2 in the myeloid compartment.