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
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| 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 |
| 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 |
Select appropriate tab below to view additional metadata details:
Project:
| Project ID: | PR002255 |
| Project DOI: | doi: 10.21228/M84V7D |
| Project Title: | Targeting the c-MYC/ELOVL6 Pathway Alters Cell Membrane Mechanics and Enhances Chemotherapeutic Efficacy in Pancreatic Cancer |
| Project 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 |
| Publications: | DOI: 10.1101/2024.11.11.622928 |
Subject:
| Subject ID: | SU003775 |
| Subject Type: | Cultured cells |
| Subject Species: | Homo sapiens |
| Taxonomy ID: | 9606 |
Factors:
Subject type: Cultured cells; Subject species: Homo sapiens (Factor headings shown in green)
| mb_sample_id | local_sample_id | Treatment |
|---|---|---|
| SA397888 | T3M4_Inh_R4 | ELOVL inhibitor |
| SA397889 | T3M4_Inh_R3 | ELOVL inhibitor |
| SA397890 | T3M4_Inh_R2 | ELOVL inhibitor |
| SA397891 | T3M4_Inh_R1 | ELOVL inhibitor |
| SA397892 | T3M4_287_R2 | shControl |
| SA397893 | T3M4_287_R1 | shControl |
| SA397894 | T3M4_287_R3 | shControl |
| SA397895 | T3M4_351_R3 | shELOVL6_1 |
| SA397896 | T3M4_351_R2 | shELOVL6_1 |
| SA397897 | T3M4_351_R1 | shELOVL6_1 |
| SA397898 | T3M4_353_R2 | shELOVL6_3 |
| SA397899 | T3M4_353_R3 | shELOVL6_3 |
| SA397900 | T3M4_353_R1 | shELOVL6_3 |
| SA397901 | T3M4_Veh_R2 | vehicle control |
| SA397902 | T3M4_Veh_R3 | vehicle control |
| SA397903 | T3M4_Veh_R4 | vehicle control |
| SA397904 | T3M4_Veh_R1 | vehicle control |
| Showing results 1 to 17 of 17 |
Collection:
| Collection ID: | CO003768 |
| Collection Summary: | Cells were kindly provided by Dr. Francisco X Real (Centro Nacional de Investigaciones Oncologicas, CNIO). https://www.cellosaurus.org/CVCL_4056 |
| Sample Type: | pancreatic ductal adenocarcinoma cells |
Treatment:
| Treatment ID: | TR003784 |
| Treatment Summary: | In this experiment, triplicates for shControl, shELOVL6 #1 and shELOVL6 #2 were generated. T3M4 cells were infected with lentiviruses containing the interference plasmid. In additon, four replicates for NT Control (non-treated) and ELOVL6-IN-2 (treated with ELOVL6 inhibitor) were generated. T3M4 cells were treated with the inhibitor for 72 hours. |
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). |
Chromatography:
| Chromatography ID: | CH004546 |
| Chromatography Summary: | Chromatographic separation was performed on a XBridge amide column (150 mm × 4.6 mm, 3.5 μm; Waters) maintained at 35°C using mobile phase A [1 mM ammonium acetate in water-acetonitrile 5:95 (v/v)] and mobile phase B [1 mM ammonium acetate in water-acetonitrile 50:50 (v/v)] in the following gradient: (0-6 min: 0% B - 6% B; 6-10 min: 6% B - 25% B; 10-11 min: 25% B - 98% B; 11-13 min: 98% B - 100% B; 13-19 min: 100% B; 19-24 min: 0% B) at a flow rate of 0.7 mL/min which was increased to 1.5 mL/min from 13 minutes onwards. |
| Instrument Name: | Shimadzu Nexera X2 |
| Column Name: | Waters Xbridge BEH Amide (150 x 4.6mm, 3.5um) |
| Column Temperature: | 35 |
| Flow Gradient: | 0-6 min: 0% B - 6% B; 6-10 min: 6% B - 25% B; 10-11 min: 25% B - 98% B; 11-13 min: 98% B - 100% B; 13-19 min: 100% B; 19-24 min: 0% B |
| Flow Rate: | 0.7 mL/min |
| Solvent A: | 5% water/95% acetonitrile; 1 mM ammonium acetate |
| Solvent B: | 50% water/50% acetonitrile; 1 mM ammonium acetate |
| Chromatography Type: | HILIC |
Analysis:
| Analysis ID: | AN005984 |
| Analysis Type: | MS |
| Chromatography ID: | CH004546 |
| Num Factors: | 5 |
| Num Metabolites: | 998 |
| Units: | nmol / mg DNA |
| Analysis ID: | AN005985 |
| Analysis Type: | MS |
| Chromatography ID: | CH004546 |
| Num Factors: | 5 |
| Num Metabolites: | 1183 |
| Units: | nmol / mg DNA |
