Lysophosphatidic acid-mediated resistance in ovarian carcinoma
Final Report Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid that occurs in multiple forms, depending on its fatty acid side chain, and interacts with six different receptors, referred to as LPAR1 – 6. The main goal of this project was to study the pathways of LPA biosynthesis and LPAR-mediated signaling in the dissemination of high grade serous carcinoma (HGSC), primarily using tumor cells and macrophages from the ascites of HGSC patient. By performing comprehensive lipidomics and database analyses we found that the concentration of distinct LPA species in ascites as well LPAR1 RNA levels in tumor tissue are associated with a poor clinical outcome, while the opposite applies to LPAR2. In agreement with these findings, our work confirmed the ability of LPA to promote invasion of cancer cells into a 3D matrix and unraveled LPAR1 in this context. We also uncovered a novel function for LPA in HGSC, namely the promotion of cell-in-cell invasion (entosis) in OC, thought to represent a nonapoptotic cell death mechanism. Intriguingly, LPA-triggered entosis required LPAR2, whose expression we found to be associated with a favorable clinical course. This points to a novel tumor-suppressive LPA-triggered pathway that is selectively eliminated in highly progressive cancers by downregulation of LPAR2. We also found a striking correlation of LPAR4 with the expression of "stemness" markers along with a short survival, pointing to a novel LPA-driven mechanism in tumor initiating cell causing metastatic spread. As LPARs represent druggable receptors, the development of highly specific agonists (e.g., for LPAR2) or antagonists (e.g., LPAR1 and 4) offers novel therapeutic opportunities for HGSC. Our lipidomic, proteomic and transcriptomic analyses showed that LPA synthesis occurs via the consecutive action of secretory phospholipases A2 followed by the phospholipase D-like autotaxin, and that tumor-associated macrophages as the main producers of PLA2G7 and autotaxin play an essential role in this pathway. These findings point to several potential strategies to interfere with LPA-triggered signaling and its impact on cancer progression. Besides the previously proposed inhibition of PLA2 and autotaxin, these include the blockade of TAM functions. Finally, we obtained novel insights into LPA-triggered signal transduction pathways by comprehensive phosphoproteomics. As part of these studies, we identified 178 LPA-induced phosphorylation events that were selectively inhibited by either a LPAR1-selective or LPAR2- selective antagonist. The functions of the affected proteins are mainly linked cytoskeleton and actin organization, migration, proliferation and metastasis and include many GTPase regulators, protein kinases and transcription factors, consistent with the invasion-promoting function of LPA . These data provide the basis for unravelling the molecular pathways underlying LPA-induced matrix invasion and entosis. Furthermore, targeting receptor-specific signaling mechanisms identified by these investigations could offer new opportunities for a pharmacological intervention with HGSC progression.
Publications
- (2017) Interferon signaling in ascites-associated macrophages is associated with a favorable clinical outcome in a subgroup of ovarian carcinoma patients. BMC Genomics 18:243
Adhikary, T., Wortmann, A., Finkernagel, F., Lieber, S., Nist, A., Stiewe, T., Wagner, U., Müller- Brüsselbach, S., Reinartz, S., Müller, R.
(See online at https://doi.org/10.1186/s12864-017-3630-9) - (2017). The unique molecular and cellular microenvironment of ovarian cancer. Front Oncol. 7:24
Worzfeld T, Pogge von Strandmann E, Huber M, Adhikary, T., Reinartz, S., Wagner, U., Müller, R.
(See online at https://doi.org/10.3389/fonc.2017.00024) - (2018). Proteotranscriptomics reveal signaling networks in the ovarian cancer microenvironment. Mol. Cell. Proteomics 17, 270-289
Worzfeld, T., Finkernagel, F., Reinartz, S., Konzer, K., Adhikary, T., Nist, A., Stiewe, T., Wagner, U., Looso, M., Graumann, J., Müller, R.
(See online at https://doi.org/10.1074/mcp.RA117.000400) - (2019). Cell-type-selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment. Mol. Oncol. 23, 185-201
Reinartz, S., Lieber, S., Pesek, J., Brandt, D.T., Asafova, A., Finkernagel, F., Watzer, B., Nockher, W.A., Nist, A., Stiewe, T., Jansen, J.M., Wagner, U., Konzer, A., Graumann, J., Grosse, R., Worzfeld, T., Müller-Brüsselbach, S. and Müller, R.
(See online at https://doi.org/10.1002/1878-0261.12396)
