Targeting ELOVL6 to disrupt c-MYC driven lipid metabolism in pancreatic cancer enhances chemosensitivity

被引：0

作者：

Garcia, Ana Garcia ^{[1
]}

Aporta, Maria Ferrer ^{[1
]}

Palma, German Vallejo ^{[2
]}

Trujillo, Antonio Giraldez ^{[2
]}

Castillo-Gonzalez, Raquel ^{[2
,3
]}

Lozano, David Calzon ^{[1
]}

Perdiguero, Alberto ^{[1
]}

Munoz Velasco, Raul ^{[1
]}

Colina Castro, Miguel ^{[1
]}

de Simone Benito, Elena ^{[1
]}

Torres-Ruiz, Raul ^{[4
,5
,6
,7
]}

Rodriguez-Perales, Sandra ^{[4
]}

Dehairs, Jonas ^{[8
]}

Swinnen, Johannes V. ^{[8
]}

Garcia-Canaveras, Juan Carlos ^{[9
]}

Lahoz, Agustin ^{[9
]}

Quiros, Sandra Montalvo ^{[10
]}

del Pozo-Rojas, Carlos ^{[10
]}

Luque Rioja, Clara ^{[11
,12
]}

Monroy, Francisco ^{[11
,12
]}

Herraez-Aguilar, Diego ^{[10
]}

Riano, Marina Alonso ^{[2
]}

Rodriguez Peralto, Jose Luis ^{[2
]}

Sanchez-Arevalo Lobo, Victor Javier ^{[1
,2
]}

机构：

[1] Univ Francisco Vitoria UFV, Fac Ciencias Expt, Grp Oncol Mol, Inst Invest Biosanit, Pozuelo De Alarcon 28223, Madrid, Spain

[2] Hosp Univ 12 Octubre, Inst Invest Sanitaria Hosp Octubre 12 imas12, Grp Oncol Cutanea Serv Anat Patol, Ave Cordoba S-N, Madrid 28041, Spain

[3] Univ Autonoma Madrid UAM, Madrid 28049, Spain

[4] Ctr Nacl Invest Oncol CNIO, Human Canc Genet Program, Mol Cytogenet & Genome Editing Unit, Madrid 28029, Spain

[5] Ctr Invest Energet Medioambientales & Tecnol CIEMA, Div Hematopoiet Innovat Therapies, Biomed Innovat Unit, Madrid 28040, Spain

[6] Inst Invest Sanitaria Fdn Jimenez Diaz, Adv Therapies Unit, Madrid 28003, Spain

[7] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain

[8] Katholieke Univ Leuven, Dept Oncol, Lab Lipid Metab & Canc, B-3000 Leuven, Belgium

[9] Hlth Res Inst La Fe, Biomarkers & Precis Med Unit, Ave Fernando Abril Martorell 106, Valencia 46026, Spain

[10] Univ Francisco Vitoria UFV, Fac Ciencias Expt, Biofis Computac & Anal Datos Biol, Inst Invest Biosanit, Pozuelo De Alarcon 28223, Madrid, Spain

[11] Univ Complutense Madrid, Dept Phys Chem, Madrid 28040, Spain

[12] Inst Biomed Res Hosp 12 Octubre, Translat Biophys, Ave Cordoba S-N, Madrid 28041, Spain

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

关键词：

CELL-MEMBRANE; RNA-SEQ; ORGANIZATION; INDENTATION; MODULATION; RESISTANCE; INHIBITION; APOPTOSIS; PATHWAYS; THERAPY;

D O I：

10.1038/s41467-025-56894-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes.

引用

页数：23

共 23 条

[21] The transcriptional regulation of TBX3 by the c-Myc/E6/E7 axis and targeting this axis for the treatment of HPV-positive cervical cancer
Macharia, L.
Khan, S.
Burmeister, C.
Goding, C.
Prince, S.
EUROPEAN JOURNAL OF CANCER, 2024, 211 : S33 - S33
[22] RING-finger protein 6 enhances c-Myc-mediated Warburg effect by promoting MAD1 degradation to facilitate pancreatic cancer metastasis
Qiu, Yumin
Zhu, Hengqing
Xu, Debin
Feng, Qian
Wen, Chongyu
Du, Yunyan
Xiang, Mingfeng
Chen, Leifeng
Peng, Xiaogang
AMERICAN JOURNAL OF CANCER RESEARCH, 2021, 11 (05): : 2025 - +
[23] Co-targeting CDK 4/6 and C-MYC/STAT3/CCND1 axis and inhibition of tumorigenesis and epithelial-mesenchymal-transition in triple negative breast cancer by Pt(II) complexes bearing NH3 as trans-co-ligand
Lv, Zhimin
Ali, Amjad
Wang, Na
Ren, Haojie
Liu, Lijing
Yan, Fufu
Shad, Man
Hao, Huifang
Zhang, Yongmin
Rahman, Faiz-Ur
JOURNAL OF INORGANIC BIOCHEMISTRY, 2024, 259

← 1 2 3 →