Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

Gouw, Arvin M.; Eberlin, Lívia S.; Margulis, Katherine; Sullivan, Delaney K.; Toal, Georgia G.; Ling, Taotao; Zare, Richard N.; Felsher, Dean W.

doi:10.1073/pnas.1617709114

Cited by 121 publications

(92 citation statements)

References 45 publications

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“…Activating mutations of KRAS drive metabolic alterations that promote tumor growth in NSCLC (21,22,24,(38)(39)(40)(41). However, the detailed molecular mechanisms by which KRAS regulates metabolism in NSCLC are not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Mutant KRAS promotes a gene expression program, which drives de novo lipogenesis in non-small cell lung cancer (21,22). In order to identify the transcriptional mechanism(s) responsible, we examined cDNA microarray data from studies of lungs of wildtype and Kras LSLG12D mice and observed a significant increase in expression of SREBP1 in lung tumors compared to normal lung (21).…”

Section: Oncogenic Kras Increases Srebp1 Expressionmentioning

confidence: 99%

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SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC

Ruiz

Montal

Haley

et al. 2020

Preprint

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Cancer cells require extensive metabolic reprogramming in order to provide the bioenergetics and macromolecular precursors needed to sustain a malignant phenotype.Mutant KRAS is a driver oncogene that is well known for its ability to regulate the ERK and PI3K signaling pathways. However, it is now appreciated that KRAS can promote tumor growth via upregulation of anabolic metabolism. We recently showed that oncogenic KRAS promotes a gene expression program of de novo lipogenesis in nonsmall cell lung cancer (NSCLC). To define the mechanism(s) responsible, we focused on the lipogenic transcription factor SREBP1. We observed that KRAS increases SREBP1 expression and genetic knockdown of SREBP1 significantly inhibited cell proliferation of mutant KRAS-expressing cells. Unexpectedly, lipogenesis was not significantly altered in cells subject to SREBP1 knockdown. Carbon tracing metabolic studies showed a significant decrease in oxidative phosphorylation and RNA-seq data revealed a significant decrease in mitochondrial encoded subunits of the electron transport chain (ETC). Taken together, these data support a novel role, distinct from lipogenesis, of SREBP1 on mitochondrial function in mutant KRAS NSCLC.3

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Section: Discussionmentioning

confidence: 99%

Section: Oncogenic Kras Increases Srebp1 Expressionmentioning

confidence: 99%

SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC

Ruiz

Montal

Haley

et al. 2020

Preprint

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“…One mechanism by which KRAS onc aberrantly regulates metabolic networks is through the reprogramming lipid metabolism by the promotion of cellular uptake, retention, accumulation, synthesis, and oxidation of fatty acids. For instance, lung cancer cells carrying the KRAS mutation are highly dependent on the activity of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) 28,189 . Mutated KRAS promotes lipogenesis through the induction of fatty acid synthase, leading to lipid signatures of human lung cancer cell lines 189 .…”

Section: Other Approachesmentioning

confidence: 99%

“…For instance, lung cancer cells carrying the KRAS mutation are highly dependent on the activity of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) 28,189 . Mutated KRAS promotes lipogenesis through the induction of fatty acid synthase, leading to lipid signatures of human lung cancer cell lines 189 . Other results have shown that the RAS mutation leads to the reprogramming of de novo lipogenesis of cancer cells by scavenging serum fatty acids 190 .…”

Section: Other Approachesmentioning

confidence: 99%

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

2019

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Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancer-related genes. Several therapeutic strategies targeting oncogenic KRAS (KRASonc) signaling pathways have been suggested, including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways, targeted RNA replacement, and oncogene-induced senescence. Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy. To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date. An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.

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“…Mass spectrometry imaging (MSI) provides spatially resolved chemical information of the surface of biological samples in a label-free manner, and has been profoundly used in preclinical, pharmaceutical and biological studies [7][8][9][10][11][12][13][14][15] . Furthermore, ambient ionization mass spectrometry imaging methods are capable of providing spatially resolved chemical information of cells and tissues with minimal sample pretreatment under atmospheric condition.…”

Section: Introductionmentioning

confidence: 99%

High Spatial Resolution Ambient Ionization Mass Spectrometry Imaging Using Microscopy Image Fusion Determines Tumor Margins

Lin

Chen

Huang

et al. 2019

Preprint

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Mass spectrometry imaging (MSI) using ambient ionization technique enables a direct chemical investigation of biological samples with minimal sample pretreatment. However, detailed morphological information of the sample is often lost due to its limited spatial resolution. We demonstrated that the fusion of ambient ionization MSI with optical microscopy of routine hematoxylin and eosin (H&E) staining produces predictive, high-resolution molecular imaging. In this study, desorption electrospray ionization (DESI) and nanospray desorption electrospray ionization (nanoDESI) mass spectrometry were emplo yed to visualize lipid and protein species on mouse tissue sections. The resulting molecular distributions obtained by ambient ionization MSI-microscopy fusion were verified with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MSI and routine immunohistochemistry (IHC) staining on the adjacent sections. Label-free molecular imaging with 5-µm spatial resolution can be achieved using DESI and nanoDESI, whereas the typical spatial resolution of ambient ionization MSI is ~100 µm. In this regard, sharpened molecular histology of tissue sections was achieved, providing complementary references to the pathology. Such multi-modality integration enabled the discovery of potential tumor biomarkers. After image fusion, we identified about 70% more potential biomarkers that could be used to determine the tumor margins on a lung tissue section with metastatic tumors. spectrometry (SIMS) MSI, were reported to achieve sharpened molecular imaging with spatial resolution at cellular level on tissue sections 36,37 . approach for image fusion was reported to be broadly applicable to different tissue type. The distribution of ions was clear at the sub-cellular level. Sharped ion images of MALDI mass spectrometry fused with microscopy of mouse tissue sections were shown in their study 37 . In addition, fusion of SIMS and electron microscopy images were also reported 38 . Although high resolution molecular distribution were revealed, these mass spectrometry methods operated under high vacuum, which limits the compatibility with conventional imaging methods for pathological examinations.In our study, an optical microscope was applied to obtain images containing meticulous details of H&E stained tissue sections. Using multivariate regression algorithm, we fused MSI with optical microscopy and generated predictive fine-grained MSI. This method was applied in different tissue types and demonstrated as a tool for cancer diagnosis. By combining optical microscopy with ambient ionization methods, DESI, and nanoDESI, for tissue mapping with image fusion, both the image resolution and image quality were greatly improved. The workflow of our study is shown in Fig. 1. ResultsElevating spatial resolution of lipid species mapping in DESI MSI. The results for fusion of DESI MSI for mouse brain and cerebellum coronal sections were shown in Fig. 2, whereas the results for mouse kidney sections were shown in Fig. 3. In Fig. 2, the dis...

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Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

Cited by 121 publications

References 45 publications

SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC

SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

High Spatial Resolution Ambient Ionization Mass Spectrometry Imaging Using Microscopy Image Fusion Determines Tumor Margins

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