Essentiality of fatty acid synthase in the 2D to anchorage-independent growth transition in transforming cells

Maria J Bueno,Jordi Capellades,Jordi Capellades,Javier Garcia-Carceles,Alejandra Junza,María Luz López-Rodríguez,Ramon Colomer,Juan P Bolaños,Juan P Bolaños,Juan P Bolaños,Alejandra Junza,Oscar Yanes,Oscar Yanes,Sara Samino,Sara Samino,Irene Lopez-Fabuel,Veronica Jimenez-Renard,Miguel Quintela-Fandino,Miguel Quintela-Fandino,Miguel Quintela-Fandino,Navdeep S Chandel

doi:10.1038/s41467-019-13028-1

Abstract

Upregulation of fatty acid synthase (FASN) is a common event in cancer, although its mechanistic and potential therapeutic roles are not completely understood. In this study, we establish a key role of FASN during transformation. FASN is required for eliciting the anaplerotic shift of the Krebs cycle observed in cancer cells. However, its main role is to consume acetyl-CoA, which unlocks isocitrate dehydrogenase (IDH)-dependent reductive carboxylation, producing the reductive power necessary to quench reactive oxygen species (ROS) originated during the switch from two-dimensional (2D) to three-dimensional (3D) growth (a necessary hallmark of cancer). Upregulation of FASN elicits the 2D-to-3D switch; however, FASN's synthetic product palmitate is dispensable for this process since cells satisfy their fatty acid requirements from the media. In vivo, genetic deletion or pharmacologic inhibition of FASN before oncogenic activation prevents tumor development and invasive growth. These results render FASN as a potential target for cancer prevention studies.

Highlights

Upregulation of fatty acid synthase (FASN) is a common event in cancer, its mechanistic and potential therapeutic roles are not completely understood
Across models driven by diverse oncogenic hits such as HER2, KRAS, or PyMT, we showed how FASN is essential for sustaining the isocitrate dehydrogenase 1 (IDH1)-dependent reductive carboxylation of glutamine[39,40] that allows quenching excessive reactive oxygen species (ROS) produced during the transition from twodimensional (2D) growth to 3D anchorage-independent growth, a hallmark of cancer[33]
FASNΔ/Δ clones were unable to form colonies, it is important to mention that minor FASN-level fluctuations observed among different FASNlox/loxPyMT clones were not related to an impaired or improved clonogenic ability (Supplementary Fig. 2a, d); similar observations applied for FASNlox/lox-KRAS and FASNlox/lox-HER2 (Supplementary Fig. 2b, c, e, f)

Summary

Introduction

Upregulation of fatty acid synthase (FASN) is a common event in cancer, its mechanistic and potential therapeutic roles are not completely understood. Genetic deletion or pharmacologic inhibition of FASN before oncogenic activation prevents tumor development and invasive growth These results render FASN as a potential target for cancer prevention studies. Complex metabolic rearrangements occur during the transition from normal to malignant cells[31] Such events require tight regulation, and changes in FASN activity might cause interferences due to the following reasons: (1) FASN activity accounts for the highest cell consumption of NADPH1, a key regulator of the REDOX balance, which is altered but highly regulated in cancer cells[32]; (2) the ability to grow in three dimensions (3D) in the absence of intercellular matrix attachment is a necessary hallmark that transforming cells must acquire to develop clinical tumors[33], and requires quenching an excess of reactive-oxygen species (ROS)34; 3) FASN consumes acetyl-. Since tumor cells can satisfy their fatty acid needs by active uptake from the bloodstream[36], we hypothesized that

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Results

Conclusion