Lysophosphatidic acid-mediated resistance in ovarian carcinoma

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Serous ovarian carcinoma has a dire prognosis and ranks fifth as the cause of death from cancer in women, mainly due to the regrowth of tumors after clinically successful first-line adjuvant chemotherapy and the selection for resistant tumor cells. The underlying mechanisms remain largely elusive, but are likely to involve chemoresistant tumor cells and spheroids floating in the peritoneal effusion (ascites). After adhesion to serous membranes, these cells invade through the mesothelium and upon contact with the extracellular matrix proliferate to form transcoelomic metastases. Multiple lines of evidence suggest that both tumor progression and therapy resistance are promoted by tumor-associated macrophages (TAMs).Human serous ovarian carcinoma represents a unique experimental system, since it not only allows the isolation of large numbers of primary tumor cells and immune cells from ascites, but also provides the opportunity to culture these cells in autologous ascites fluid without any artificial additives. Using this system, we have been able to isolate from the ascites of individual untreated patients chemoresistant as well as chemosensitive tumor cell spheroids. Moreover, chemotherapy of the chemosensitive spheroids results in the selection of chemoresistant cells, thus providing systems for the studying both primary and therapy-induced resistance. Comparative RNA-Seq experiments led to the association of the lysophosphatidic acid (LPA) receptor gene LPAR3 with chemoresistance, and identified LPAR6 as a TAM-specific receptor gene. The enzymatic generation of LPA, a known mediator of poor clinical outcome, is critically dependent on secreted phospholipases A2 and autotaxin. Our RNA-Seq analyses showed that TAMs express several genes coding for these enzyme (PLA2G7, ENPP2) at much higher levels than tumor cells, pointing to a cooperation between both cell types in LPA-mediated signaling. Based on these observations we propose to address the following specific goals:(i) We will systematically study LPA signaling components in tumor cells, TAMs and ascites fluid and will investigate potential associations with tumor relapse (Reinartz).(ii) We will define LPAR-triggered signaling pathways in these cells by establishing transcriptional signaling networks and analyzing the function of specific signaling components (Müller).(iii) We will address the role of LPA signaling pathways in chemoresistance and matrix interaction (Müller).(iv) We will analyze the role of LPA in the polarization of TAMs and the putative cooperation of tumor cells and TAMs in LPA generation and signaling in co-culture systems (Reinartz).Ultimately, the goal of this project is to provide the basis for an optimal clinical development of drugs directed at the LPA signaling network and an improvement of the adjuvant therapy of ovarian cancer.