PAK4 signaling in development and cancer

Our understanding of cancer biology has been evolving rapidly shaped by groundbreaking discoveries. We now understand that cancer is not one disease but many, and that tumors are not foreign objects in the human body but rather the result of changes in the previously normal tissues and organs. Thus, in order to ask fundamental questions and dissect the complexity of cancer it is essential to grasp how the healthy organs develop and function and the cellular and molecular mechanisms involved. The serine/threonine PAKs are signaling hubs with proven roles in development and disease. Specifically, they are important to several hallmarks of cancer. Thus, the family in general, and PAK4 in particular, is increasingly attracting the interest of the scientific community.

In this thesis I have explored the role of PAK4 in normal organ development and cancer. Novel mouse models with PAK4 depletion in the mammary gland and in the pancreas have been established and characterized in Paper I and Paper II. The absence of major tissue abnormalities upon PAK4 depletion in the mammary epithelium allowed me to use this model to study the role of PAK4 in tumorigenesis in vivo, in Paper III, and a counterpart mouse model with PAK4 overexpression in the mammary epithelium was also generated. These complementary in vivo setups showed that PAK4-overexpressing mammary glands occasionally developed mammary tumors while PAK4 abrogation impaired PyMT-driven mammary tumorigenesis. Extensive in vitro experiments, using state of the art techniques, then supported a model in which PAK4 confers selective advantages to cancer cells by overcoming the senescence barrier. This, in turn, constitutes a selective vulnerability of cancer cells that become susceptible to a senescence-like response upon PAK4 inhibition. The data presented also demonstrates a crosstalk between PAK4 and NF-κB signaling, and a direct interaction and phosphorylation site within the REL-homology domain of RELB is found to be relevant for tuning RELB-mediated transcription and cancer cell proliferation via C/EBPβ. Importantly, these findings were largely supported by correlations in clinical data and validated ex vivo in patient-derived cells, thus highlighting PAK4 as an attractive therapeutic opportunity in cancer. Therefore, this thesis contributes to a better understanding of the mechanisms that govern breast tumorigenesis, with hopes that such knowledge will prove relevant in cancer prognosis and treatment.

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. *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. Tânia Costa, Ting Zhuang, Julie Lorent, Emilia Turco, Helene Olofsson, Miriam Masia-Balague, Miao Zhao, Parisa Rabieifar, Neil Robertson, Raoul Kuiper, Jonas Sjölund, Matthias Spiess, Pablo Hernández-Varas, Uta Rabenhorst, Pernilla Roswall, Ran Ma, Xiaowei Gong, Johan Hartman, Kristian Pietras, Peter D. Adams, Paola Defilippi and Staffan Strömblad. (2019). PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer. Nature Communications. 10, 3589.
https://doi.org/10.1038/s41467-019-11510-4