LKB1 is a master kinase, which regulates a variety of cellular pathways, thus influencing cell polarity, cell migration, cell proliferation and cellular metabolism. Mutations in lkb1 are associated with the Peutz-Jeghers-Syndrome, a rare dominant autosomal inherited cancer syndrome disease, in which patients develop benign gastrointestinal harmatomas and show a higher risk for intestinal and extraintestinal cancer. Notably, deletion of the lkb1 locus or downregulation of the protein expression is frequently found in various cancer specimen and -cell lines (with a few exceptions, (Cidlinsky et al., 2016)).

We found that LKB1 is not a constitutively active kinase but that its activity and protein stability is regulated by binding to the phospholipid phosphatidic acid (Dogliotti et al., 2017).In ongoing projects, we investigate the regulation of LKB1 and other kinases by phospholipids of the membrane using biochemistry approaches as well as super resolution microscopy and FRET-analyses. We further aim to elucidate the role of LKB1 in the regulation of cell polarity on the one hand and its impact on cell proliferation control and cellular metabolism on the other hand. We recently identified several potential interaction partners of LKB1 in a mass spectroscopy-approach, which are currently investigated for their role in cell polarity, cell proliferation and cellular metabolism.

Picture: Taken from Dogliotti et al. Nat Commun. 2017 Jun 26;8:15747. doi: 10.1038/ncomms15747, ©Creative Commons Attribution 4.0 International License.

During metastasis, cancer cells lose their cell--cell contacts and apical-basal polarity. The cell-cell jucntion protein E-cadherin is already frequently used as a prognostic marker of (de)differentiation in the immunohistopathological analysis of several types of carcinoma.

We found that the Tight Junction adapter protein Pals1 is frequently downregulated in colorectal cancer specimen and that decreased expression of Pals1 correlates with poorer patients' survival (Lüttgenau et al. Molecular Cancer 2021). Furthermore, we generated a cell culture model with Pals1-Knockout and found Pals1-deficient cells to migrate and invade faster and to form more metastases in a mouse transplantation model. Dissecting the molecular pathomechanism, we demonstrated that Pals1 functions in redundancy to SMAP1 to inhibit the small GTPase Arf6, which inactivates Rac1, which in turn controls cell migration (Lüttgenau et al. Molecular Cancer 2021, Harms et al. Cancer Gene Therapy 2022).

In our future projects, we aim to elucidate the molecular mechanisms how Pals1 and other adapter proteins of the TJ regulate cell migration and metastasis as well as pro-proliferative signaling pathways.

For that, we use CRISPR/Cas9 gene editing in established cancer cell lines as well as intestinal organoids and biopsies of cancer specimen.

In vertebrates, blood filtration and secretion is accomplished within the same organ – the kidney. In Drosophila, the filtrating cell, the so called “nephrocytes” are separated from the secreting cells - the first are located within the body cavity, the latter are integrated in the “Malpighian tubules”. Whereas many studies have been performed describing several aspects of the development of the Malpighian tubules, little is known about the nephrocytes. Therefore, we are currently characterizing the role of cell polarity determinants in this cell type in order to reveal important mechanism, which are essential for the establishment of the filtration barrier (Hochapfel et al., 2017 and 2018, Heiden et al. 2021, Gass et al. 2022). Notably, Drosophila nephrocytes are an emerging model system to study (kidney) diseases such as diabetic nephropathy and chronic kidney disease.