Role of ANGPTL4 in ovarian carcinoma
Hematology, Oncology
Final Report Abstract
Unexpectedly, biologically active recombinant ANGPTL4 was no longer available from commercial sources after the start of the project, initially due to delivery bottlenecks caused the pandemic, and later due to discontinuation of the originally used product by the supplier. We therefore focused on BCAM, which is linked to OC in a similar way as ANGPTL4, i.e., by promoting OC metastasis-associated processes. The role of BCAM in OC had not been addressed at the start of the project. Our data show that BCAM negatively regulates the compactness of tumor cell spheroids, and consequently triggers the dispersion of spheroids in a collagen matrix, facilitates the clearance of mesothelial cells at spheroid attachment sites and promotes the trans-mesothelial invasion of tumor cells from spheroids into explanted omental tissue. We also obtained strong evidence suggesting that BCAM acts as a decoy rather than a signaling receptor to modulate metastasis-related functions on OC cells. Furthermore, we have identified ADAM10 as a major BCAM sheddase produced by OC cells and identified proteolytic cleavage sites yielding a soluble BCAM isoform exclusively composed of the extracellular domain. Mechanistically, all BCAM forms interfered with interaction of laminin a5 (LAMA5) and integrinb1. This interference loosens the structure of spheroids, thereby promoting their dispersion and metastatic colony formation at target sites. This conclusion is consistent with the observed colonization-enhancing effect of BCAM in both explanted omentum and a mouse model, as well as the highly significant association of BCAM with a poor clinical outcome of OC. Our data not only provide new mechanistic insights into OC biology, but may also contribute to novel therapeutic strategies impacting peritoneal metastasis formation. We also pursued a second project in parallel to the work described above, which focused on the regulation of metastasis-associated processes by lysophosphatidic-acid (LPA), another mediator whose concentration in the OC microenvironment is strongly associated with a poor clinical outcome survival. This work revealed a pivotal role for Rho kinase (ROCK), protein kinase C (PKC) and ERK in the LPA-induced phosphorylation of MYPT1, a regulatory subunit of protein phosphatase 1, which in turn is a crucial regulator of myosin light chain (MLC2). Phosphorylation of MYPT1 at kinase-specific sites was found to regulate the activity of MLC2, thereby promoting actomyosin dynamics, cancer cell migration and entosis. These findings provide a compelling link of LPA signaling to OC progression and a poor survival. The identification of MYPT1 as a pivotal mediator of OC progression may facilitate the development of novel therapeutic options, as the selective targeting of MYPT1-regulated PP1 activity is likely to be more efficient than pan-PP1 inhibitors, which in previous clinical trials were unsuccessful due to the broad range of proteins targeted by PP1.
Publications
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Basal cell adhesion molecule promotes metastasis‐associated processes in ovarian cancer. Clinical and Translational Medicine, 13(1).
Sivakumar, Suresh; Lieber, Sonja; Librizzi, Damiano; Keber, Corinna; Sommerfeld, Leah; Finkernagel, Florian; Roth, Katrin; Reinartz, Silke; Bartsch, Jörg W.; Graumann, Johannes; Müller‐Brüsselbach, Sabine & Müller, Rolf
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The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis. Theranostics, 13(6), 1921-1948.
Ojasalu, Kaire; Lieber, Sonja; Sokol, Anna M.; Nist, Andrea; Stiewe, Thorsten; Bullwinkel, Imke; Finkernagel, Florian; Reinartz, Silke; Müller-Brüsselbach, Sabine; Grosse, Robert; Graumann, Johannes & Müller, Rolf
