Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.

Animals Mice Humans Pancreatic Neoplasms / drug therapy Asparagine / metabolism Adenocarcinoma / drug therapy Symbiosis Tumor Microenvironment Pancreatic Neoplasms

Journal

Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119

Informations de publication

Date de publication:
11 2022
Historique:
received: 07 06 2022
accepted: 12 10 2022
pubmed: 22 11 2022
medline: 30 11 2022
entrez: 21 11 2022
Statut: ppublish

Résumé

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Identifiants

DOI: 10.1038/s43018-022-00463-1 PMID: 36411320 PMC: PMC9701142
pubmed: 36411320
doi: 10.1038/s43018-022-00463-1
pii: 10.1038/s43018-022-00463-1
pmc: PMC9701142
doi:

Substances chimiques

Asparagine 7006-34-0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1386-1403

Subventions

Organisme : NCI NIH HHS
ID : R01 CA248160
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA237421
Pays : United States
Organisme : Cancer Research UK
ID : A19258
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A25236
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA244931
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022. The Author(s).

Références

Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
pubmed: 31912902 doi: 10.3322/caac.21590
Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).
pubmed: 22439937 pmcid: 3371414 doi: 10.1016/j.ccr.2012.01.007
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
pubmed: 25644265 pmcid: 4316379 doi: 10.1158/0008-5472.CAN-14-2211
Halbrook, C. J. & Lyssiotis, C. A. Employing metabolism to improve the diagnosis and treatment of pancreatic cancer. Cancer Cell 31, 5–19 (2017).
pubmed: 28073003 doi: 10.1016/j.ccell.2016.12.006
Waters, A. M. & Der, C. J. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb. Perspect. Med 8, a031435 (2018).
pubmed: 29229669 pmcid: 5995645 doi: 10.1101/cshperspect.a031435
Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).
pubmed: 23535601 pmcid: 3656466 doi: 10.1038/nature12040
Ying, H. Q. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).
pubmed: 22541435 pmcid: 3472002 doi: 10.1016/j.cell.2012.01.058
Daemen, A. et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc. Natl Acad. Sci. USA 112, E4410–E4417 (2015).
pubmed: 26216984 pmcid: 4538616 doi: 10.1073/pnas.1501605112
Lyssiotis, C. A. & Kimmelman, A. C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 27, 863–875 (2017).
pubmed: 28734735 pmcid: 5814137 doi: 10.1016/j.tcb.2017.06.003
Halbrook, C. J., Pasca di Magliano, M. & Lyssiotis, C. A. Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G27–G35 (2018).
pubmed: 29543507 pmcid: 6109710 doi: 10.1152/ajpgi.00416.2017
Auciello, F. R. et al. A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov. 9, 617–627 (2019).
pubmed: 30837243 pmcid: 6497553 doi: 10.1158/2159-8290.CD-18-1212
Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).
pubmed: 27509858 pmcid: 5228623 doi: 10.1038/nature19084
Halbrook, C. J. et al. Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab. 29, 1390–1399 (2019).
pubmed: 30827862 pmcid: 6602533 doi: 10.1016/j.cmet.2019.02.001
Dalin, S. et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res 79, 5723–5733 (2019).
pubmed: 31484670 pmcid: 7357734 doi: 10.1158/0008-5472.CAN-19-0960
Boyer, S. et al. Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF–PI3K pathway. eLife 11, e73796 (2022).
pubmed: 35156921 pmcid: 8843093 doi: 10.7554/eLife.73796
Huang, H. et al. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell 40, 656–673 (2022).
pubmed: 35523176 doi: 10.1016/j.ccell.2022.04.011
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).
pubmed: 31197017 pmcid: 6727976 doi: 10.1158/2159-8290.CD-19-0094
Hutton, C. et al. Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell 39, 1227–1244 (2021).
pubmed: 34297917 pmcid: 8443274 doi: 10.1016/j.ccell.2021.06.017
Grunwald, B. T. et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 184, 5577–5592 (2021).
pubmed: 34644529 doi: 10.1016/j.cell.2021.09.022
Liudahl, S. M. et al. Leukocyte heterogeneity in pancreatic ductal adenocarcinoma: phenotypic and spatial features associated with clinical outcome. Cancer Discov. 11, 2014–2031 (2021).
pubmed: 33727309 pmcid: 8338775 doi: 10.1158/2159-8290.CD-20-0841
Hosein, A. N. et al. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 5, e129212 (2019).
pubmed: 31335328 doi: 10.1172/jci.insight.129212
Bernard, V. et al. Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression. Clin. Cancer Res. 25, 2194–2205 (2019).
pubmed: 30385653 doi: 10.1158/1078-0432.CCR-18-1955
Peng, J. Y. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 29, 725–738 (2019).
pubmed: 31273297 pmcid: 6796938 doi: 10.1038/s41422-019-0195-y
Li, J. et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49, 178–193 (2018).
pubmed: 29958801 pmcid: 6707727 doi: 10.1016/j.immuni.2018.06.006
Guillaumond, F. et al. Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 3919–3924 (2013).
pubmed: 23407165 pmcid: 3593894 doi: 10.1073/pnas.1219555110
Digman, M. A., Caiolfa, V. R., Zamai, M. & Gratton, E. The phasor approach to fluorescence lifetime imaging analysis. Biophys. J. 94, L14–L16 (2008).
pubmed: 17981902 doi: 10.1529/biophysj.107.120154
Krall, A. S. et al. Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell Metab. 33, 1013–1026 (2021).
pubmed: 33609439 pmcid: 8102379 doi: 10.1016/j.cmet.2021.02.001
Sullivan, M. R. et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife 8, e44235 (2019).
pubmed: 30990168 pmcid: 6510537 doi: 10.7554/eLife.44235
Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552–563 (2015).
pubmed: 26232225 pmcid: 4522278 doi: 10.1016/j.cell.2015.07.017
McCarthy A et al. Tumour cell heterogeneity instructs fibroblast diversity and reciprocal signalling. Cell Syst. https://doi.org/10.2139/ssrn.3486019 (2019).
Pathria, G. et al. Translational reprogramming marks adaptation to asparagine restriction in cancer. Nat. Cell Biol. 21, 1590–1603 (2019).
pubmed: 31740775 pmcid: 7307327 doi: 10.1038/s41556-019-0415-1
Tameire, F. et al. ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat. Cell Biol. 21, 889–899 (2019).
pubmed: 31263264 pmcid: 6608727 doi: 10.1038/s41556-019-0347-9
Barbosa-Tessmann, I. P. et al. Activation of the human asparagine synthetase gene by the amino acid response and the endoplasmic reticulum stress response pathways occurs by common genomic elements. J. Biol. Chem. 275, 26976–26985 (2000).
pubmed: 10856289 doi: 10.1016/S0021-9258(19)61468-7
Mick, E. et al. Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell. eLife 9, e49178 (2020).
pubmed: 32463360 pmcid: 7255802 doi: 10.7554/eLife.49178
Steele, N. G. et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat. Cancer 1, 1097–1112 (2020).
pubmed: 34296197 pmcid: 8294470 doi: 10.1038/s43018-020-00121-4
Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014).
pubmed: 25242145 pmcid: 4224619 doi: 10.1016/j.molcel.2014.08.018
Sullivan, L. B. et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat. Cell Biol. 20, 782–788 (2018).
pubmed: 29941931 pmcid: 6051729 doi: 10.1038/s41556-018-0125-0
Birsoy, K. et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540–551 (2015).
pubmed: 26232224 pmcid: 4522279 doi: 10.1016/j.cell.2015.07.016
Douer, D. et al. Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood 109, 2744–2750 (2007).
pubmed: 17132721 doi: 10.1182/blood-2006-07-035006
Wolthers, B. O. et al. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study. Lancet Oncol. 18, 1238–1248 (2017).
pubmed: 28736188 doi: 10.1016/S1470-2045(17)30424-2
Marin-Valencia, I. et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 15, 827–837 (2012).
pubmed: 22682223 pmcid: 3372870 doi: 10.1016/j.cmet.2012.05.001
Hayashi, M. et al. Microenvironmental activation of Nrf2 restricts the progression of Nrf2-activated malignant tumors. Cancer Res. 80, 3331–3344 (2020).
pubmed: 32636316 doi: 10.1158/0008-5472.CAN-19-2888
Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).
pubmed: 27609895 pmcid: 5245791 doi: 10.1126/science.aaf5171
Hensley, C. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).
pubmed: 26853473 pmcid: 4752889 doi: 10.1016/j.cell.2015.12.034
Lee, S. W. et al. EGFR–Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis. Dev. Cell 50, 381–392 (2019).
pubmed: 31257175 pmcid: 6684838 doi: 10.1016/j.devcel.2019.05.043
Elgogary, A. et al. Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proc. Natl Acad. Sci. USA 113, E5328–E5336 (2016).
pubmed: 27559084 pmcid: 5018752 doi: 10.1073/pnas.1611406113
Kishimoto, S. et al. Imaging of glucose metabolism by
pubmed: 31408004 pmcid: 6706239 doi: 10.7554/eLife.46312
Tasdogan, A. et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115–120 (2020).
pubmed: 31853067 doi: 10.1038/s41586-019-1847-2
McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017).
pubmed: 28092686 pmcid: 5695682 doi: 10.1038/ng.3753
Sancho, P. et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab. 22, 590–605 (2015).
pubmed: 26365176 doi: 10.1016/j.cmet.2015.08.015
Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).
pubmed: 25119024 pmcid: 4376130 doi: 10.1038/nature13611
Rajeshkumar, N. V. et al. Treatment of pancreatic cancer patient-derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin. Clin. Cancer Res. 23, 5639–5647 (2017).
pubmed: 28611197 pmcid: 6540110 doi: 10.1158/1078-0432.CCR-17-1115
Zeidan, A., Wang, E. S. & Wetzler, M. Pegasparaginase: where do we stand. Expert Opin. Biol. Ther. 9, 111–119 (2009).
pubmed: 19063697 doi: 10.1517/14712590802586058
Hammel, P. et al. Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: an open-label, randomized Phase IIb trial. Eur. J. Cancer 124, 91–101 (2020).
pubmed: 31760314 doi: 10.1016/j.ejca.2019.10.020
Molina, J. R. et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 24, 1036–1046 (2018).
pubmed: 29892070 doi: 10.1038/s41591-018-0052-4
Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).
pubmed: 31699883 pmcid: 7023461 doi: 10.1126/science.aav2588
Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438 (2018).
pubmed: 29337136 pmcid: 5803449 doi: 10.1016/j.cmet.2017.12.006
Krall, A. S., Xu, S., Graeber, T. G., Braas, D. & Christofk, H. R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457 (2016).
pubmed: 27126896 pmcid: 4855534 doi: 10.1038/ncomms11457
Garcia-Bermudez, J. et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat. Cell Biol. 20, 775–781 (2018).
pubmed: 29941933 pmcid: 6030478 doi: 10.1038/s41556-018-0118-z
Kanai, Y. et al. The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol. Aspects Med. 34, 108–120 (2013).
pubmed: 23506861 doi: 10.1016/j.mam.2013.01.001
Davis, R. T. et al. Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. Nat. Cell Biol. 22, 310–320 (2020).
pubmed: 32144411 doi: 10.1038/s41556-020-0477-0

Auteurs

Christopher J Halbrook (CJ)

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. chris.halbrook@uci.edu.
University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA. chris.halbrook@uci.edu.
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. chris.halbrook@uci.edu.
Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. chris.halbrook@uci.edu.
ORCID: 0000-0002-3376-3114

Galloway Thurston (G)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Seth Boyer (S)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Cecily Anaraki (C)

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.

Jennifer A Jiménez (JA)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Amy McCarthy (A)

Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

Nina G Steele (NG)

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Department of Surgery, Henry Ford Health System, Detroit, MI, USA.

Samuel A Kerk (SA)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
ORCID: 0000-0001-9786-2245

Hanna S Hong (HS)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
ORCID: 0000-0003-1202-2808

Lin Lin (L)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Fiona V Law (FV)

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.

Catherine Felton (C)

Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

Lorenzo Scipioni (L)

Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.

Peter Sajjakulnukit (P)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
ORCID: 0000-0002-8556-7481

Anthony Andren (A)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Alica K Beutel (AK)

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.

Rima Singh (R)

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.

Barbara S Nelson (BS)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Fran Van Den Bergh (F)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
ORCID: 0000-0003-4025-6863

Abigail S Krall (AS)

Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.

Peter J Mullen (PJ)

Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.

Li Zhang (L)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Sandeep Batra (S)

Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.

Jennifer P Morton (JP)

Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Ben Z Stanger (BZ)

Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Heather R Christofk (HR)

Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
ORCID: 0000-0002-8662-4425

Michelle A Digman (MA)

Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
ORCID: 0000-0003-4611-7100

Daniel A Beard (DA)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Andrea Viale (A)

Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ji Zhang (J)

Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
ORCID: 0000-0002-9274-1767

Howard C Crawford (HC)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Department of Surgery, Henry Ford Health System, Detroit, MI, USA.

Marina Pasca di Magliano (M)

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.

Claus Jorgensen (C)

Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

Costas A Lyssiotis (CA)

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
ORCID: 0000-0001-9309-6141

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Differential integrated stress response and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Differential integrated stress response and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Differential integrated stress response and...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Differential integrated stress response and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Asparagine › Differential integrated stress response and...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Differential integrated stress response and...
questionsmedicales.fr › Phénomènes biologiques › Symbiose › Differential integrated stress response and...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Differential integrated stress response and...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Differential integrated stress response and...