New Perspectives on Cancer Applicability of Falcon Systems Studies of Lipotoxicity
Lexiang Yu1*
1Department of Pathology and Cell Biology, Columbia University, New York, USA
*Correspondence to: Lexiang Yu, PhD, Associated Scientist, Department of Pathology and Cell Biology, Columbia University, 116th and Broadway, New York 10027, USA; Email: ly2519@cumc.columbia.edu
Abstract
The groundbreaking study “Falcon systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity” explores the complex relationship between free fatty acids (FFAs) and lipotoxicity. By utilizing the Functional Analysis of Lipid Composition (Falcon) platform, researchers gained fresh insights into the role of FFAs in various diseases. The study offered a tool to explore cancer and its metabolic changes, including increased de novo lipogenesis, upregulated fatty acid transporters, and altered β-oxidation. Lipotoxicity, the accumulation of excessive lipids in non-adipose tissues, was identified as a pivotal factor in cancer progression, impairing cellular function and promoting inflammation. Targeting lipotoxicity could disrupt crucial pathways in cancer cells and improve treatment outcomes. Overall, the Falcon study highlights the importance of understanding and addressing lipotoxicity in diseases, offering potential avenues for innovative therapies and improving the cancer-lipotoxicity mechanism explore strategies.
Keywords: Falcon, lipotoxicity, cancer, metabolism, free fatty acids
1 INTRODUCTION
Researchers have shed light on the complex world of free fatty acids (FFAs) and their connection with lipotoxicity in a ground-breaking article titled “Falcon systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity”[1]. The study, which made use of the Functional Analysis of Lipid Composition (Falcon) platform, a cell-based platform for the unbiased, multimodal investigation of structurally diverse FFAs found in human plasma, offered a fresh viewpoint and explores the novel lipotoxic mediator in multi-disciplinary. It supported the development of fatty acid libraries at the cellular level as well as the discovery of new lipotoxic fatty acids, fatty acid omics, lipotoxicity identification, and lipid metabolism in applicability to other disease models. This research holds promise for novel lipotoxicity intervention approaches and has significant implications for our understanding of metabolic disorders.
Mounting evidence suggests that alterations in fatty acid metabolism play a critical role in the initiation, growth, and spread of various cancers[2-5]. Cancer cells exhibit distinct metabolic changes, including increased de novo lipogenesis, which synthesizes fatty acids from non-lipid sources[6]. Targeting de novo lipogenesis[7] enzymes (such as fatty acid synthase[8] and stearoyl-CoA desaturase-1[9]) could hinder cancer cell growth[10,11]. Additionally, cancer cells upregulate fatty acid transporters to scavenge lipids from the tumor environment, promoting aggressive tumor phenotypes[5,12]. Moreover, cancer cells manipulate β-oxidation for energy production and accumulate lipid droplets, contributing to cancer progression and therapy resistance[13]. Understanding and disrupting these processes offer potential avenues for targeted cancer therapies.
Lipotoxicity[14] characterized by the accumulation of excessive lipid molecules in non-adipose tissues, plays a pivotal role in cancer development and progression[13,15]. Excessive lipid accumulation can impair mitochondrial function, induce endoplasmic reticulum (ER) stress, and disrupt cellular membranes[16,17]. These disruptions lead to cellular dysfunction, genomic instability, and perturbation of lipid rafts and signaling molecules involved in cell proliferation, survival, and metastasis. Furthermore, lipotoxicity contributes to the inflammatory microenvironment within tumors by triggering the release of pro-inflammatory cytokines, this perpetuates a cycle of inflammation that fuels tumor growth and invasion[18,19].
Given the significance of lipotoxicity in cancer progression, researchers are exploring strategies to mitigate lipotoxicity in cancer cells. Inhibiting key enzymes involved in fatty acid synthesis and uptake, such as citrate / isocitrate carrier, ATP-citrate lyase, acetyl-CoA carboxylase and fatty acid transporters, shows promise in limiting lipid accumulation and disrupting tumor growth[20]. Enhancing lipid breakdown through β-oxidation or stimulating lipophagy, the selective autophagic degradation of lipids, is being investigated as potential therapeutic interventions[16]. These approaches aim to restore lipid homeostasis and counteract lipotoxicity-related effects in cancer cells. By targeting lipotoxicity, it may be possible to disrupt crucial pathways involved in cancer progression and improve treatment outcomes, which are systematical identified novel mediators of lipotoxicity through Falcon.
2 CONCLUSION
The groundbreaking Falcon study has provided new insights into the role of FFAs and lipotoxicity never limited to in insulin-related pancreatic cancer cell study[1]. It highlights the significance of fatty acid metabolism in cancer initiation, growth, and spread. Lipotoxicity emerges as a key contributor to cancer progression through impairing cellular functions, inducing inflammation, and perturbing signaling pathways. Targeting lipotoxicity by modulating fatty acid synthesis, uptake, and breakdown holds promise as a therapeutic strategy to counteract these effects. By understanding and disrupting lipotoxicity-associated processes, researchers can pave the way for innovative and targeted cancer therapies, potentially improving patient outcomes in the future.
Acknowledgements
Not applicable.
Conflicts of Interest
The author declared no conflict of interest.
Author Contribution
Yu L contributed to the manuscript and approved the final version.
Abbreviation List
Falcon, Functional Analysis of Lipid Composition
FFAs, Free fatty acids
References
[1] Wieder N, Fried JC, Kim C et al. Falcon systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity. Cell Metab, 2023; 35: 887-905. [DOI]
[2] Munir R, Lisec J, Swinnen JV et al. Lipid metabolism in cancer cells under metabolic stress. Br J Cancer, 2019; 120: 1090-1098. [DOI]
[3] Kamphorst JJ, Cross JR, Fan J et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci USA, 2013; 110: 8882-8887. [DOI]
[4] Furuta E, Pai SK, Zhan R et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res, 2008; 68: 1003-1011. [DOI]
[5] Bergers G, Fendt SM. The metabolism of cancer cells during metastasis. Nat Rev Cancer, 2021; 21: 162-180. [DOI]
[6] Simeone P, Tacconi S, Longo S et al. Expanding Roles of De Novo Lipogenesis in Breast Cancer. Int J Environ Res Public Health, 2021; 18: 3575. [DOI]
[7] Ameer F, Scandiuzzi L, Hasnain S et al. De novo lipogenesis in health and disease. Metabolism, 2014; 63: 895-902. [DOI]
[8] Schcolnik-Cabrera A, Chávez-Blanco A, Domínguez-Gómez G et al. Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. Expert Opin Investig Drugs, 2018; 27: 475-489. [DOI]
[9] Ascenzi F, Vitis C, Maugeri-Saccà M et al. SCD1, autophagy and cancer: implications for therapy. J Exp Clin Cancer Res, 2021; 40: 265. [DOI]
[10] Zadra G, Photopoulos C, Tyekucheva S et al. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol Med, 2014; 6: 519-538. [DOI]
[11] Zadra G, Ribeiro CF, Chetta P et al. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. Proc Natl Acad Sci USA, 2019; 116: 631-640. [DOI]
[12] Ringel AE, Drijvers JM, Baker GJ et al. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell, 2020; 183: 1848-1866. [DOI]
[13] Petan T. Lipid Droplets in Cancer. Rev Physiol Biochem Pharmacol, 2023; 185: 53-86. [DOI]
[14] Engin AB. What Is Lipotoxicity? Adv Exp Med Biol, 2017; 960: 197-220. [DOI]
[15] Fernández LP, Cedrón MG, Molina AR. Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment. Front Oncol, 2020; 10: 577420. [DOI]
[16] Zhang S, Peng X, Yang S et al. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis, 2022; 13: 132. [DOI]
[17] Herpen NA, Schrauwen-Hinderling VB. Lipid accumulation in non-adipose tissue and lipotoxicity. Physiol Behav, 2008; 94: 231-241. [DOI]
[18] Jang JH, Kim DH, Surh YJ. Dynamic roles of inflammasomes in inflammatory tumor microenvironment. NPJ Precis Oncol, 2021; 5: 18. [DOI]
[19] Gómez-Valenzuela F, Escobar E, Pérez-Tomás R et al. The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition. Front Oncol, 2021; 11: 686792. [DOI]
[20] Batchuluun B, Pinkosky SL, Steinberg GR. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat Rev Drug Discov, 2022; 21: 283-305. [DOI]
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