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    Online Resource
    Online Resource
    Abstract C077: Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 22_Supplement ( 2022-11-15), p. C077-C077
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    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. C077-C077
    Abstract: Tumor growth is inevitably accompanied by changes in the tumor-microenvironment to which cancer cells have to adapt in order to thrive. Alterations in metabolism and blood perfusion of solid tumors have been suggested to drive a spontaneous increase in tumoral temperature. However, it is currently unknown if this phenomenon affects cancer biology. We found increased temperature in human pancreatic ductal adenocarcinoma (PDAC) tumors. By mimicking this observation in PDAC cell lines, we found that cancer cells adapt to tumoral temperature by altering the cellular lipidome and accordingly evade ferroptosis, a lipid-dependent form of cell death. We found evidence that tumoral temperature-induced ferroptosis evasion depends on p38-MAPK deactivation and ultimately drives resistance to the chemotherapeutic drug gemcitabine. Collectively, our findings suggest a direct role for p38-dependend ferroptosis evasion in gemcitabine resistance, and we identify tumoral temperature as a pathophysiological driver of this process. Our discovery unveils temperature as an unexplored hallmark of the tumor-microenvironment. Citation Format: Vincent de Laat, Halit Topal, Jonas Dehairs, Xander Spotbeen, Ali Talebi, Frank Vanderhoydonc, Tessa Ostyn, Tania Roskams, Baki Topal, Johan Swinnen. Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C077.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA22-C077
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Online Resource
    Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Experimental & Clinical Cancer Research Vol. 42, No. 1 ( 2023-04-19)
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    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 42, No. 1 ( 2023-04-19)
    Abstract: One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance. Methods Using gene expression analysis and mass spectrometry-based lipidomics of BRAF-mutant melanoma cell lines, melanoma PDX and clinical data sets, we explored the association of FASN expression with membrane lipid poly-unsaturation and therapy-resistance. Next, we treated therapy-resistant models with a preclinical FASN inhibitor TVB-3664 and a panel of ROS inducers and performed ROS analysis, lipid peroxidation tests and real-time cell proliferation assays. Finally, we explored the combination of MAPK inhibitors, TVB-3664 and arsenic trioxide (ATO, as a clinically used ROS-inducer) in Mel006 BRAF mutant PDX as a gold model of therapy resistance and assessed the effect on tumor growth, survival and systemic toxicity. Results We found that FASN expression is consistently increased upon the onset of therapy resistance in clinical melanoma samples, in cell lines and in Mel006 PDX and is associated with decreased lipid poly-unsaturation. Forcing lipid poly-unsaturation in therapy-resistant models by combining MAPK inhibition with FASN inhibition attenuated cell proliferation and rendered cells exquisitely sensitive to a host of ROS inducers. In particular, the triple combination of MAPK inhibition, FASN inhibition, and the clinical ROS-inducing compound ATO dramatically increased survival of Mel006 PDX models from 15 to 72% with no associated signs of toxicity. Conclusions We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    URL: Article
    DOI: 10.1186/s13046-023-02664-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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