Regulation of cell differentiation and invasion by members of the TGFß family

Sammanfattning: Transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are important in embryonic development and tissue homeostasis, but also have complex roles in the context of cancer. TGFβ promotes epithelial to mesenchymal transition (EMT) a physiological developmental process, often hijacked in different types of cancer, eventually leading to cancer cell invasion and metastasis. BMP signaling is involved in bone formation, angiogenesis and neural cell differentiation, but also regulates cancer by inducing EMT and its reversion. Liver kinase B1 (LKB1) is a tumor suppressor protein kinase involved in the regulation of cell metabolism, proliferation and polarity. First, we investigated how LKB1 negatively regulates BMP signaling and we demonstrated that LKB1 interacts with one of the BMP type I receptors and mediates its degradation, leading to the inhibition of BMP-induced cell differentiation.We then focused on the role of LKB1 in the establishment of mammary epithelial polarity. Upon LKB1 depletion, normal mammary epithelial cells lost the ability to form polarized acini, and displayed enhanced TGFβ responses. The use of a chemical inhibitor targeting TGFβ type I receptor restored the formation of acini, therefore we concluded that the contribution of LKB1 to mammary epithelial polarity is dependent on the regulation of autogenous TGFβ signaling.Glioblastoma (GBM) is a brain malignancy, that is highly invasive and heterogeneous in terms of cell differentiation. TGFβ enhances the self-renewal potential of glioblastoma stem cells (GSCs), while BMP promotes their differentiation towards the astrocytic lineage. In the second part of this thesis, we investigated the role of different effectors downstream of TGFβ/BMP signaling in GBM. Snail is a well-established inducer of EMT in carcinomas but in the context of GBM, we demonstrated that Snail was induced by BMP7, and via its interaction with Smad signaling effectors, enhanced BMP while it suppressed TGFβ signaling, thus promoting the astrocytic differentiation of GSCs and suppressing stemness.Finally, the role of the TGFβ/BMP target gene, CXXC5, was investigated in GBM. CXXC5 expression was enriched in GSCs that express high levels of stem cell markers, and depletion of CXXC5 led to reduced self-renewal capacity of GBM cells. Further analysis indicated that CXXC5 epigenetically regulates stemness-related genes by counteracting the activity of the polycomb repressor complex 2 (PRC2), thus affecting the histone modification pattern on the regulatory elements of these genes. Collectively, the thesis provides evidence on mechanisms that regulate cell differentiation by interfering with TGFβ/BMP signaling.

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