The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer
Open accessAbstract
Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial–mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the up-regulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation–induced EMT, cell motility, and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“extracellular asparagine from serum and produced by a constitutively active integrated stress response in subpopulations of PDAC cells can be targeted using asparaginase, potently sensitizing PDAC tumors to mitochondrial inhibition in pre-clinical models239,246.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [239]
In the citing paper
“Differential activation of the integrated stress response can also be used to define sub-populations within individual tumors, which drives differential sensitivity to metabolic inhibitors239.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [239]
In the citing paper
“metabolic characterization of clonal lines isolated from tumors revealed that two distinct populations can co-exist within the same tumor239”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [239]
In the citing paper
“asparagine produced by subpopulations of PDAC cells that have a constitutively active integrated stress response support the mitochondrial metabolism of other PDAC cells during limited respiration239, providing a barrier to metabolic targeting.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [239]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364
Metascape provides a biologist-oriented resource for the analysis of systems-level datasets
Zhou, Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A. H., Tanaseichuk, O., Benner, C., & Chanda, S. K. (2019) · Nature Communications · doi:10.1038/s41467-019-09234-6 · Cited by 14,611
Molecular mechanisms of epithelial–mesenchymal transition
Lamouille, S., Xu, J., & Derynck, R. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3758 · Cited by 8,091
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A., & Thiery, J. P. (2016) · Cell · doi:10.1016/j.cell.2016.06.028 · Cited by 4,492
Genomic analyses identify molecular subtypes of pancreatic cancer
Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., et al. (2016) · Nature · doi:10.1038/nature16965 · Cited by 3,621
The integrated stress response
Pakos‐Zebrucka, K., Koryga, I., Mnich, K., Ljujic, M., Samali, A., & Gorman, A. M. (2016) · The EMBO Reports · doi:10.15252/embr.201642195 · Cited by 2,659
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609
Regulatory networks defining EMT during cancer initiation and progression
Craene, B. D., & Berx, G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3447 · Cited by 2,487
Moffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G. H., Hoadley, K. A., Rashid, N. U., Williams, L. A., Eaton, S. C., Chung, A. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3398 · Cited by 2,194
EMT and Dissemination Precede Pancreatic Tumor Formation
Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., Reichert, M., Beatty, G. L., Rustgi, A. K., Vonderheide, R. H., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.025 · Cited by 2,136
Zheng, X., Carstens, J. L., Kim, J., Scheible, M., Kaye, J. A., Sugimoto, H., Wu, C.-C., LeBleu, V. S., & Kalluri, R. (2015) · Nature · doi:10.1038/nature16064 · Cited by 2,018
Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway
Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., et al. (2013) · Nature · doi:10.1038/nature12040 · Cited by 1,990
Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy
Collisson, E. A., Sadanandam, A., Olson, P., Gibb, W. J., Truitt, M., Gu, S., Cooc, J., Weinkle, J., Kim, G. E., Jakkula, L., et al. (2011) · Nature Medicine · doi:10.1038/nm.2344 · Cited by 1,967
Glucose feeds the TCA cycle via circulating lactate
Hui, S., Ghergurovich, J. M., Morscher, R. J., Jang, C., Teng, X., Lu, W., Esparza, L. A., Reya, T., Zhan, L., Yanxiang Guo, J., et al. (2017) · Nature · doi:10.1038/nature24057 · Cited by 1,721
Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis
Lu, W., & Kang, Y. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.04.010 · Cited by 1,039
Krebs, A. M., Mitschke, J., Losada, M. L., Schmalhofer, O., Boerries, M., Busch, H. S., Böttcher, M., Mougiakakos, D., Reichardt, W., Bronsert, P., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3513 · Cited by 1,008
Bayne, L. J., Beatty, G. L., Jhala, N., Clark, C. E., Rhim, A. D., Stanger, B. Z., & Vonderheide, R. H. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.025 · Cited by 947 · cited 2×
“KPC cells originated from Pdx1-Cre; LSL-KRasG12D/+; LSL-Tp53R172H/+ mice were kindly provided by Dr. Robert H. Vonderheide (University of Pennsylvania, Philadelphia, PA; Bayne et al., 2012) and subcloned in our laboratory to give rise to the KPC#65 clone used in this study.”
MethodKamphorst, J. J., Nofal, M., Commisso, C., Hackett, S. R., Lu, W., Grabocka, E., Vander Heiden, M. G., Miller, G., Drebin, J. A., Bar-Sagi, D., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2211 · Cited by 893
Self-citationSnail blocks the cell cycle and confers resistance to cell deathPreprint
Vega, S., Morales, A. V., Ocaña, O. H., Valdés, F., Fabregat, I., & Nieto, M. A. (2004) · Genes & Development · doi:10.1101/gad.294104 · Cited by 866
Glutamine Metabolism in Cancer: Understanding the Heterogeneity
Cluntun, A. A., Lukey, M. J., Cerione, R. A., & Locasale, J. W. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.01.005 · Cited by 796
EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration
Aiello, N. M., Maddipati, R., Norgard, R. J., Balli, D., Li, J., Yuan, S., Yamazoe, T., Black, T. A., Sahmoud, A., Furth, E. E., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.05.027 · Cited by 734
Pharmacological brake-release of mRNA translation enhances cognitive memory
Sidrauski, C., Acosta‐Alvear, D., Khoutorsky, A., Vedantham, P., Hearn, B. R., Li, H., Gamache, K., Gallagher, C. M., Ang, K. K. H., Wilson, C. G. M., et al. (2013) · eLife · doi:10.7554/elife.00498 · Cited by 716
Ye, J., Kumanova, M., Hart, L. S., Sloane, K. L., Zhang, H., Panis, D. N. D., Bobrovnikova-Marjon, E. V., Diehl, J. A., Ron, D., & Koumenis, C. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.81 · Cited by 709
Kurrey, N. K., Jalgaonkar, S. P., Joglekar, A. V., Ghanate, A. D., Chaskar, P. D., Doiphode, R. Y., & Bapat, S. A. (2009) · Stem Cells · doi:10.1002/stem.154 · Cited by 655
Hosios, A. M., Hecht, V. C., Danai, L. V., Johnson, M. O., Rathmell, J. C., Steinhauser, M. L., Manalis, S. R., & Vander Heiden, M. G. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.02.012 · Cited by 641
Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features
Puleo, F., Nicolle, R., Blum, Y., Cros, J., Marisa, L., Demetter, P., Quertinmont, E., Svrcek, M., Elarouci, N., Iovanna, J., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.08.033 · Cited by 563
Badea, L., Herlea, V., Dima, S., Dumitraşcu, T., & Popescu, I. (2008) · PubMed · Cited by 531
Khanna, C. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh261 · Cited by 476
Asparagine Plays a Critical Role in Regulating Cellular Adaptation to Glutamine Depletion
Zhang, J., Fan, J., Venneti, S., Cross, J. R., Takagi, T., Bhinder, B., Djaballah, H., Kanai, M., Cheng, E. H., Judkins, A. R., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.018 · Cited by 439
Hotz, B., Arndt, M., Dullat, S., Bhargava, S., Buhr, H.-J., & Hotz, H. G. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2926 · Cited by 426
Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma
Wu, W.-S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M., & Look, A. T. (2005) · Cell · doi:10.1016/j.cell.2005.09.029 · Cited by 409
Pan, M., Reid, M. A., Lowman, X. H., Kulkarni, R. P., Tran, T. Q., Liu, X., Yang, Y., Hernandez-Davies, J. E., Rosales, K. K., Li, H., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3410 · Cited by 368
Metabolic reprogramming and epithelial‐to‐mesenchymal transition in cancer
Sciacovelli, M., & Frezza, C. (2017) · FEBS Journal · doi:10.1111/febs.14090 · Cited by 334
Analyzing Cell Death by Nuclear Staining with Hoechst 33342Preprint
Crowley, L. C., Marfell, B. J., & Waterhouse, N. J. (2016) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot087205 · Cited by 323
Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism
Biancur, D. E., Paulo, J. A., Małachowska, B., Quiles Del Rey, M., Sousa, C. M., Wang, X., Sohn, A. S. W., Chu, G. C., Gygi, S. P., Harper, J. W., et al. (2017) · Nature Communications · doi:10.1038/ncomms15965 · Cited by 315
Falletta, P., Sánchez‐del‐Campo, L., Chauhan, J. S., Effern, M., Kenyon, A., Kershaw, C. J., Siddaway, R., Lisle, R., Freter, R., Daniels, M. J., et al. (2017) · Genes & Development · doi:10.1101/gad.290940.116 · Cited by 260
Upholding a role for EMT in pancreatic cancer metastasis
Aiello, N. M., Brabletz, T., Kang, Y., Nieto, M. A., Weinberg, R. A., & Stanger, B. Z. (2017) · Nature · doi:10.1038/nature22963 · Cited by 260
We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine
Lemberg, K. M., Vornov, J. J., Rais, R., & Slusher, B. S. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-1148 · Cited by 234
Gwinn, D. M., Lee, A. G., Briones-Martin-del-Campo, M., Conn, C. S., Simpson, D. R., Scott, A. I., Le, A., Cowan, T. M., Ruggero, D., & Sweet-Cordero, E. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.12.003 · Cited by 230
A Role for p53 in the Adaptation to Glutamine Starvation through the Expression of SLC1A3
Tajan, M., Hock, A. K., Blagih, J., Robertson, N. A., Labuschagne, C. F., Kruiswijk, F., Humpton, T. J., Adams, P. D., & Vousden, K. H. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.005 · Cited by 230
Chen, H., Zhu, G., Li, Y., Padia, R. N., Dong, Z., Pan, Z. K., Liu, K., & Huang, S. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1950 · Cited by 184
EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis
Lee, S.-W., Zhang, Y., Jung, M., Cruz, N., Alas, B., & Commisso, C. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.05.043 · Cited by 172
Self-citationGaglio, D., Soldati, C., Vanoni, M., Alberghina, L., & Chiaradonna, F. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004715 · Cited by 164
Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming
García‐Jiménez, C., & Goding, C. R. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.11.018 · Cited by 157
Molecular regulation of Snai2 in development and disease
Zhou, W., Gross, K. M., & Kuperwasser, C. (2019) · Journal of Cell Science · doi:10.1242/jcs.235127 · Cited by 109
Translational reprogramming marks adaptation to asparagine restriction in cancer
Pathria, G., Lee, J. S., Hasnis, E., Tandoc, K. V., Scott, D. A., Verma, S. K., Feng, Y., Larue, L., Sahu, A. D., Topisirović, I., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0415-1 · Cited by 103
Molecular markers associated with outcome and metastasis in human pancreatic cancer
den broeck, A. V., Vankelecom, H. E. J., van Eijsden, R. G. E., Govaere, O., & Topal, B. (2012) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-31-68 · Cited by 86
Glutamate and asparagine cataplerosis underlie glutamine addiction in melanoma
Ratnikov, B. I., Aza‐Blanc, P., Ronai, Z. A., Smith, J. W., Osterman, A. L., & Scott, D. A. (2015) · Oncotarget · doi:10.18632/oncotarget.3132 · Cited by 80
Thiaville, M. M., Pan, Y., Gjymishka, A., Zhong, C., Kaufman, R. J., & Kilberg, M. S. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708320200 · Cited by 62
Adhim, Z., Matsuoka, T., Bito, T., Shigemura, K., Lee, K.-M., Kawabata, M., Fujisawa, M., Nibu, K., & Shirakawa, T. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.262 · Cited by 59
Sandhu, V., Lothe, I. M. B., Labori, K. J., Lingjærde, O. C., Buanes, T. A., Dalsgaard, A. M., Skrede, M., Hamfjord, J., Haaland, T., Eide, T. J., et al. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.12.002 · Cited by 43
Liu, S., Ye, D., Xu, D., Liao, Y., Zhang, L., Liu, L., Yu, W., Wang, Y., He, Y., Hu, J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7940 · Cited by 43
Selection of Metastatic Breast Cancer Cells Based on Adaptability of Their Metabolic State
Singh, B., Tai, K., Madan, S., Raythatha, M. R., Cady, A. M., Braunlin, M., Irving, L. R., Bajaj, A., & Lucci, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036510 · Cited by 28
Villarino, N., Signaevskaia, L., van Niekerk, J., Medal, R., Kim, H., Lahmy, R., Scully, K. M., Pinkerton, A. B., Kim, S. W., Lowy, A. M., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.18587 · Cited by 16
Self-citationSandhu, V., Lothe, I. M. B., Labori, K. J., Lingjærde, O. C., Buanes, T. A., Dalsgaard, A. M., Skrede, M. L., Hamfjord, J., Haaland, T., Eide, T. J., et al. (2015) · Pancreatology · doi:10.1016/j.pan.2015.05.118 · Cited by 15
Flagged first, then by citations
Cited by
Sorted by citations
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
Wang, Z., Liu, F., Fan, N., Zhou, C., Li, D., MacVicar, T., Dong, Q., Bruns, C. J., & Zhao, Y. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.589508 · Cited by 189
Metabolic heterogeneity in cancer
Demicco, M., Liu, X., Leithner, K., & Fendt, S. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00963-z · Cited by 186
Harnessing metabolic dependencies in pancreatic cancers
Encarnación-Rosado, J., & Kimmelman, A. C. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00431-7 · Cited by 190
The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression
Fedele, M., Sgarra, R., Battista, S., Cerchia, L., & Manfioletti, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020800 · Cited by 171
Metadata
- Authors
- Recouvreux, M. V., Moldenhauer, M. R., Galenkamp, K. M. O., Jung, M., James, B., Zhang, Y., Lowy, A., Bagchi, A., & Commisso, C.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of California San Diego (US)
- Corresponding author
- Commisso, Cosimo
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2020-06-08
- Volume
- 217
- Issue
- 9
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC7478719
- OpenAlex
- W3032930460
- Cited by
- 181
- References
- 57
- Citations by year
- 2026: 15 · 2025: 33 · 2024: 28 · 2023: 37 · 2022: 40 · 2021: 23 · 2020: 4
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA207189)
- National Cancer Institute (P30CA030199)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- glutamine deprivation, Slug, epithelial-mesenchymal transition, pancreatic ductal adenocarcinoma, nutritional stress, metabolic stress, MEK/ERK signaling, ATF4, metastasis, cell motility, tumor progression
- MeSH terms
- Snail Family Transcription Factors, Adenocarcinoma, Animals, Cell Movement, Cell Survival, Glutamine, Humans, Mice, Inbred C57BL, Neoplasm Metastasis, Pancreatic Neoplasms, RNA, Messenger, Stress, Physiological, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, MAP Kinase Signaling System, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Activating Transcription Factor 4, HEK293 Cells, Epithelial-Mesenchymal Transition
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
