Summary of Study ST003645

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002255. The data can be accessed directly via it's Project DOI: 10.21228/M84V7D This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php

Study ID	ST003645
Study Title	Targeting the c-MYC/ELOVL6 Pathway Alters Cell Membrane Mechanics and Enhances Chemotherapeutic Efficacy in Pancreatic Cancer
Study Summary	Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, marked by a survival rate of only 12%. Consequently, the exploration of novel therapeutic strategies becomes a critical clinical imperative. Among the genetic alterations contributing to PDAC, c-MYC (an oncogenic transcription factor) overexpression arises due to upstream mutations, amplifications, and copy number alterations. c-MYC serves as a key regulator in the tumor's metabolic reprogramming, playing a pivotal role in proliferation, migration, and metastasis. This study delves into the investigation of the role of the elongase ELOVL6 in c-MYC-induced cell transformation and its potential as a therapeutic target in PDAC. Here, we demonstrate that c-MYC regulates lipid elongation to promote cell transformation, offering a new avenue for therapeutic intervention. Initially, we show the direct regulation of ELOVLs expression by c-MYC in various PDAC mouse models and cell lines, elucidating its upregulation during transformation and tumor progression. Genetic or chemical inhibition of ELOVL6 results in decreased proliferation and migration, accompanied by alterations in fatty acid elongation. These changes in fatty acid composition led to modifications in membrane rigidity, permeability, and thickness, which collectively affect micropinocytosis and macropinocytosis. Importantly, we observe an increase in Abraxane uptake and a synergistic effect when combined with ELOVL6 interference in vitro. In vivo validation demonstrates that ELOVL6 inhibition significantly reduces tumor growth and enhances the response to Abraxane, thereby increasing overall survival. Altogether, these results position ELOVL6 as a promising therapeutic target in the treatment of PDAC.
Institute	Universidad Francisco de Vitoria - Hospital 12 de Octubre
Last Name	Sánchez-Arévalo Lobo
First Name	Víctor Javier
Address	Carretera Pozuelo-Majadahonda, km 1,800, Pozuelo de Alarcón, Madrid, 28223, Spain
Email	victor.sanchezarevalo@ufv.es
Phone	+34 91 709 14 00
Submit Date	2024-12-22
Raw Data Available	Yes
Raw Data File Type(s)	mzML
Analysis Type Detail	LC-MS
Release Date	2025-01-26
Release Version	1

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Sample Preparation:

Sampleprep ID:	SP003782
Sampleprep Summary:	An amount of cells containing 10 μg of DNA was homogenized in 700 μL of water with a handheld sonicator and was mixed with 800 μl HCl(1M):CH3OH 1:8 (v/v), 900 μl CHCl3, 200 μg/ml of the antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT; Sigma Aldrich) and 3 μl of UltimateSPLASH™ ONE internal standard mix (#330820, Avanti Polar Lipids) and 3 μl of SphingoSPLASH™ I internal standard mix (#330734, Avanti Polar Lipids). After vortexing and centrifugation, the lower organic fraction was collected and evaporated using a Savant Speedvac spd111v (Thermo Fisher Scientific) at room temperature and the remaining lipid pellet was stored at - 20°C under argon. Just before mass spectrometry analysis, lipid pellets were reconstituted in 100% ethanol. Lipid species were analyzed by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) on a Nexera X2 UHPLC system (Shimadzu) coupled with hybrid triple quadrupole/linear ion trap mass spectrometer (6500+ QTRAP system; AB SCIEX).

Sampleprep ID:

SP003782

Sampleprep Summary:

An amount of cells containing 10 μg of DNA was homogenized in 700 μL of water with a handheld sonicator and was mixed with 800 μl HCl(1M):CH3OH 1:8 (v/v), 900 μl CHCl3, 200 μg/ml of the antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT; Sigma Aldrich) and 3 μl of UltimateSPLASH™ ONE internal standard mix (#330820, Avanti Polar Lipids) and 3 μl of SphingoSPLASH™ I internal standard mix (#330734, Avanti Polar Lipids). After vortexing and centrifugation, the lower organic fraction was collected and evaporated using a Savant Speedvac spd111v (Thermo Fisher Scientific) at room temperature and the remaining lipid pellet was stored at - 20°C under argon. Just before mass spectrometry analysis, lipid pellets were reconstituted in 100% ethanol. Lipid species were analyzed by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) on a Nexera X2 UHPLC system (Shimadzu) coupled with hybrid triple quadrupole/linear ion trap mass spectrometer (6500+ QTRAP system; AB SCIEX).