PAK4 in organ development and cancer initiation

Tumors are complex organs with a unique ecosystem containing tumor cells entangled with various infiltrating cells. Tumors have distinct signaling signatures, which confers upon it the ability to grow in the primary host organ and further disseminate to other parts of the body. Tumors are a heterogeneous mix of sub-clones raised through genetic evolution. Concurrently, strong evidence suggests that nongenetic variables such as developmental cues add to this functional heterogeneity within individual tumors. Interestingly, multiple pathways involved in human organ development are restored and upregulated in various adult cancer. p21-activated kinase 4 (PAK4) is a downstream effector of the Cdc42 and Rac1 small Rho family GTPases. PAK4 is involved in embryonic development, but its expression is also upregulated in different cancer types. Formerly, reverse genetic efforts to study PAK4 have been hampered due to the embryonic lethality under the complete depletion of PAK4. Consequently, multiple conditional Pak4 knockout murine models have been developed to study the possible role of PAK4 in various stages of tissue development.

The overall aim of this thesis is to explore the role of PAK4 in breast and pancreas organ development and to dissect its role in the formation of pancreatic ductal adenocarcinoma (PDAC). In paper I, we dissected the role of PAK4 in mammary gland development. Conditional Pak4 gene depletion in the murine mammary gland did not affect this organ’s normal physiology or development. Moreover, Pak4 depletion was dispensable for normal murine pancreas development and whole-body hemostasis maintenance paper II. Therefore, the mouse model developed in paper II was further crossed with the Pdx-Cre; K-rasG12D/+ model to investigate the role of Pak4 in PDAC formation in paper III. We demonstrate in paper III that Pak4 depletion significantly reduces the formation of preneoplastic lesions via inhibition of KrasG12D-driven acinar to ductal reprogramming (ADR). The aforementioned halt is accompanied by increased senescence-like growth arrest and decreased apoptosis. Notably, PAK4 gene expression was higher in human PDAC tumors than the normal tissue, and its protein expression was elevated in human pancreatic intraepithelial neoplasia (PanIN) and PDAC compared with the normal tissues. In sum, this thesis improves our understanding of the role of PAK4 in organ development and provides insight into the possible role of PAK4 in PDAC initiation and progression.

List of scientific papers

I. Parisa Rabieifar, Ting Zhuang, Tânia Costa, Miao Zhao and Staffan Strömblad (2019). Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion. Scientific Reports. 9, 14436. *Parisa Rabieifar and Ting Zhuang contributed equally.
https://doi.org/10.1038/s41598-019-50819-4

II. Miao Zhao, Parisa Rabieifar, Tânia Costa, Ting Zhuang, Audrey Minden, Matthias Löhr, Rainer Heuchel and Staffan Strömblad (2017). Pdx1-Credriven conditional gene depletion suggests PAK4 as dispensable for mouse pancreas development. Scientific Reports. 7, 7031.
https://doi.org/10.1038/s41598-017-07322-5

III. Parisa Rabieifar, Miao Zhao, Carlos. F. Moro, Tânia D.F. Costa, Bela Bozoky, Nicholas P Tobin, Matthias Löhr, Rainer Heuchel, Daniel Öhlund, Staffan Strömblad. PAK4 governs Kras-driven premalignant acinar cell reprogramming. [Manuscript]