1 research outputs found
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