To become resistant, cancer cells need to activate and maintain molecular defense mechanisms that depend on an energy trade-off between resistance and essential functions. Metabolic reprogramming has been shown to fuel cell growth and contribute to cancer drug resistance. Recently, changes in lipid metabolism have emerged as an important driver of resistance to anticancer agents. In this review, we highlight the role of choline metabolism with a focus on the phosphatidylcholine cycle in the regulation of resistance to therapy. We analyze the contribution of phosphatidylcholine and its metabolites to intracellular processes of cancer cells, both as the major cell membrane constituents and source of energy. We further extended our discussion about the role of phosphatidylcholine-derived lipid mediators in cellular communication between cancer and immune cells within the tumor microenvironment, as well as their pivotal role in the immune regulation of therapeutic failure. Changes in phosphatidylcholine metabolism are part of an adaptive program activated in response to stress conditions that contribute to cancer therapy resistance and open therapeutic opportunities for treating drug-resistant cancers.

Cancer cells are characterized by their eximious ability to adapt and survive within harsh microenvironments (poor oxygenation and nutrient deprivation). Cancer metabolic plasticity is among the adaptive responses that allow tumor development in these conditions and also contribute to therapy resistance. The first tumor metabolic adaptation was identified by Otto Warburg in the 1920s, who described that cancer cells have an exacerbated glucose uptake and glycolysis accompanied by increased lactate production even under aerobic conditions (1). Since this pioneering work, known as the “Warburg effect”, much effort has been made to exploit the unique features of tumor metabolic phenotypes and metabolic reprogramming that is currently well-recognized as one of the hallmarks of cancer (2, 3). In recent years, lipid metabolism reprogramming has received renewed interest in the cancer field, and compelling evidence reveals the contribution of lipid remodeling in regulating the hallmarks of cancer (4).

Uncontrolled cell division exhibited by cancer cells introduces a cellular metabolic challenge, since it is necessary to double the total biomass (nucleic acid, proteins, and lipids) to support the mitotic cell division of a single cell into two equal-sized daughter cells. Cancer cells reprogram their metabolism from catabolism to anabolism to attend to this energetic and biomass demand to fuel cell proliferation (5). Among the biomolecules that compose total cell biomass, lipids have received fewer research efforts mainly due to their extremely diverse structure that turns their detection and quantification an analytical challenge. However, this scenario has changed due to technological progress in analytical approaches for lipid investigation that helped to gain a comprehensive look at the complexity and singularity of tumor lipid metabolism (6). Advances in two main analytical techniques, magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) often coupled to liquid chromatography (LC) systems, contributed to the identification of abnormal choline (Cho) metabolism in tumors. Over the past four decades, accumulating evidence of MRS studies evaluating total choline (tCho) metabolite levels in cancer cells, notably free choline (Cho), phosphocholine (PCho), and glycerophosphocholine (GPC), revealed the importance of choline metabolism in tumor biology. Almost every tumor cell type investigated showed increased levels of tCho metabolites compared to non-malignant counterparts (7–15).

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Keywords: lipid metabolism, phosphatidylcholine, lipid mediators, immunoregulation, immune microenvironment, cancer drug resistance

Citation: Saito RF, Andrade LNS, Bustos SO and Chammas R (2022) Phosphatidylcholine-Derived Lipid Mediators: The Crosstalk Between Cancer Cells and Immune Cells. Front. Immunol. 13:768606. doi: 10.3389/fimmu.2022.768606

Received: 31 August 2021; Accepted: 13 January 2022;Published: 15 February 2022.

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Copyright © 2022 Saito, Andrade, Bustos and Chammas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Roger Chammas, [email protected]