Abstract
The sphingolipid and lysophosphatidate regulatory networks impact diverse mechanisms attributed to cancer cells and the tumor immune microenvironment. Deciphering the complexity demands implementation of a holistic approach combined with higher-resolution techniques. We implemented a multi-modular integrative approach consolidating the latest accomplishments in gene expression profiling, prognostic/predictive modeling, next generation digital pathology, and systems biology for epithelial ovarian cancer. We assessed patient-specific transcriptional profiles using the sphingolipid/lysophosphatidate/immune-associated signature. This revealed novel sphingolipid/lysophosphatidate-immune gene-gene associations and distinguished tumor subtypes with immune high/low context. These were characterized by robust differences in sphingolipid‐/lysophosphatidate-related checkpoints and the drug response. The analysis also nominates novel survival models for stratification of patients with CD68, LPAR3, SMPD1, PPAP2B, and SMPD2 emerging as the most prognostically important genes. Alignment of proprietary data with curated transcriptomic data from public databases across a variety of malignancies (over 600 categories; over 21,000 arrays) showed specificity for ovarian carcinoma. Our systems approach identified novel sphingolipid-lysophosphatidate-immune checkpoints and networks underlying tumor immune heterogeneity and disease outcomes. This holds great promise for delivering novel stratifying and targeting strategies.
Highlights
Cellular sphingosine 1-phosphate (S1P)/ceramide rheostat is a decisive checkpoint. (IX) We reported the multidimensional contribution of the sphingolipid machinery to the mechanisms underlying the pathological epithelial to mesenchymal transition (EMT) program during metastasis [33]. (X) The sphingolipid system is druggable at multiple checkpoints
The starting point of the integrative MuSiCO is the assembling of the multigene signature and its application for real-timePCR-based gene expression profiling of clinically well-characterized patient material as described previously in detail [33,49]
The sphingolipid/ lysophosphatidate/immune-associated 38/8-gene signature that we applied includes the families of S1P and LPA receptors, the interconnected gene network of sphingolipid-metabolizing enzymes within the sphingomyelin/salvage pathway and the LPA metabolizing enzymes, genes encoding the MHC-like molecules involved in lipid presentation and a set of immune-related genes
Summary
There is a lack of clear molecular criteria to stratify (group) the patients for effective application of molecular-targeted agents, including immunotherapeutic interventions Advanced techniques such as nanoString, CIBERSORT and Immunoscore are capable of stratifying patients according to molecular- or immune-related criteria and subsequently predicting disease outcome [11,12,13]. These techniques have provided unprecedented perspectives in decoding heterogeneity of several tumor types. There is no breakthrough in understanding of serous ovarian cancer For this aggressive type of cancer, there is a particular need to continue searching for new pathways/ targets for therapeutic modulation and new effective strategies to stratify patients to risk groups. We will provide a novel approach to this challenge based on the understanding of the dysregulation of the sphingolipid signaling system that occurs in cancer, its crosstalk with the lysophosphatidate system, and the interrelation with the local tumor immune microenvironment
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