BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma

Abstract

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1,2,3,4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA–BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: BCAT2 is critical for PDAC development.
Fig. 2: BCAT2-mediated BCAA catabolism is essential for PDAC.
Fig. 3: Reduced BCAT2 expression does not affect histone acetylation in pancreas ductal cells.
Fig. 4: KRAS suppresses BCAT2 ubiquitylation and degradation.
Fig. 5: BCAT2 inhibitor or low-BCAA diet impedes PDAC.

Data availability

Mass spectrometry data have been deposited in ProteomeXchange with the primary accession code PXD016611. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data for Figs. 1–5 and Extended Data Figs. 1, 3, 6 and 810 are provided with the paper.

References

  1. 1.

    Halbrook, C. J. & Lyssiotis, C. A. Employing metabolism to improve the diagnosis and treatment of pancreatic cancer. Cancer Cell 31, 5–19 (2017).

    CAS  Article  Google Scholar 

  2. 2.

    Mayers, J. R. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20, 1193–1198 (2014).

    CAS  Article  Google Scholar 

  3. 3.

    Dey, P. et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature 542, 119–123 (2017).

    CAS  Article  Google Scholar 

  4. 4.

    Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).

    CAS  Article  Google Scholar 

  5. 5.

    Ichihara, A. & Koyama, E. Transaminase of branched chain amino acids. I. Branched chain amino acids-α-ketoglutarate transaminase. J. Biochem. 59, 160–169 (1966).

    CAS  Article  Google Scholar 

  6. 6.

    Taylor, R. T. & Jenkins, W. T. Leucine aminotransferase. II. Purification and characterization. J. Biol. Chem. 241, 4396–4405 (1966).

    CAS  PubMed  Google Scholar 

  7. 7.

    Shimomura, Y., Murakami, T., Nakai, N., Nagasaki, M. & Harris, R. A. Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise. J. Nutr. 134, 1583S–1587S (2004).

    CAS  Article  Google Scholar 

  8. 8.

    Neinast, M., Murashige, D. & Arany, Z. Branched chain amino acids. Annu Rev Physiol 81, 139–164 (2019).

    CAS  Article  Google Scholar 

  9. 9.

    Adsay, N. V., Basturk, O., Cheng, J. D. & Andea, A. A. Ductal neoplasia of the pancreas: nosologic, clinicopathologic, and biologic aspects. Semin. Radiat. Oncol. 15, 254–264 (2005).

    Article  Google Scholar 

  10. 10.

    Reichert, M. & Rustgi, A. K. Pancreatic ductal cells in development, regeneration, and neoplasia. J. Clin. Invest. 121, 4572–4578 (2011).

    CAS  Article  Google Scholar 

  11. 11.

    Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

    CAS  Article  Google Scholar 

  12. 12.

    Deng, H. et al. Discovery and optimization of potent, selective, and in vivo efficacious 2-aryl benzimidazole BCATm inhibitors. ACS Med. Chem. Lett. 7, 379–384 (2016).

    CAS  Article  Google Scholar 

  13. 13.

    Carrer, A. et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 9, 416–435 (2019).

    Article  Google Scholar 

  14. 14.

    Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    CAS  Article  Google Scholar 

  15. 15.

    Pohl, C. & Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 366, 818–822 (2019).

    CAS  Article  Google Scholar 

  16. 16.

    Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019).

    CAS  Article  Google Scholar 

  17. 17.

    Yang, L. et al. E3 ligase Trim21 ubiquitylates and stabilizes keratin 17 to Induce STAT3 activation in psoriasis. J. Invest. Dermatol. 138, 2568–2577 (2018).

    CAS  Article  Google Scholar 

  18. 18.

    Esposito, D., Koliopoulos, M. G. & Rittinger, K. Structural determinants of TRIM protein function. Biochem. Soc. Trans. 45, 183–191 (2017).

    CAS  Article  Google Scholar 

  19. 19.

    Wallenhammar, A. et al. Solution NMR structure of the TRIM21 B-box2 and identification of residues involved in its interaction with the RING domain. PLoS ONE 12, e0181551 (2017).

    Article  Google Scholar 

  20. 20.

    Sabile, A. et al. Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol. Cell. Biol. 26, 5994–6004 (2006).

    CAS  Article  Google Scholar 

  21. 21.

    Chen, V. C., Kristensen, A. R., Foster, L. J. & Naus, C. C. Association of connexin43 with E3 ubiquitin ligase TRIM21 reveals a mechanism for gap junction phosphodegron control. J. Proteome Res. 11, 6134–6146 (2012).

    CAS  Article  Google Scholar 

  22. 22.

    Hornbeck, P. V. et al. PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 40, D261–D270 (2012).

    CAS  Article  Google Scholar 

  23. 23.

    Hornbeck, P. V. et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).

    CAS  Article  Google Scholar 

  24. 24.

    Ma, T. K., McAdoo, S. P. & Tam, F. W. Spleen tyrosine kinase: a crucial player and potential therapeutic target in renal disease. Nephron 133, 261–269 (2016).

    CAS  Article  Google Scholar 

  25. 25.

    Tang, C. & Zhu, G. Classic and novel signaling pathways involved in cancer: Targeting the NF-κB and Syk signaling pathways. Curr. Stem. Cell Res. Ther. 14, 219–225 (2019).

    CAS  Article  Google Scholar 

  26. 26.

    Solon-Biet, S. M. et al. Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nat. Metab. 1, 532–545 (2019).

    Article  Google Scholar 

  27. 27.

    Gao, X. et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat. Commun. 7, 11960 (2016).

    CAS  Article  Google Scholar 

  28. 28.

    Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).

    CAS  Article  Google Scholar 

  29. 29.

    Yang, X. M. et al. Overexpression of Rac GTPase activating Protein 1 contributes to proliferation of cancer cells by reducing hippo signaling to promote cytokinesis. Gastroenterology 155, 1233–1249, doi:2018.

  30. 30.

    Hong, J. et al. CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma. J. Clin. Invest. 122, 2165–2175 (2012).

    CAS  Article  Google Scholar 

  31. 31.

    Zhang, Y. et al. Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone. Autophagy 13, 538–553 (2017).

    CAS  Article  Google Scholar 

  32. 32.

    Wang, Y. P. et al. Arginine Methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer. Mol. Cell 64, 673–687 (2016).

    CAS  Article  Google Scholar 

  33. 33.

    Yang, H. B. et al. Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer. Nat. Commun. 6, 6973 (2015).

    CAS  Article  Google Scholar 

  34. 34.

    Li, F. et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell 27, 698–711 (2015).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank J. Cheng (Shanghai Jiaotong University) and H. Ji (Chinese Academy of Sciences, Shanghai, China) for providing Pdx1-Cre and LSL-KrasG12D mouse lines, respectively34; T. Kang (Sun Yat-sen University, Guangzhou, China30) for rabbit anti-human SYK antibody; J. Qin for insightful discussions; members of the Fudan Cancer Metabolism laboratory for discussions throughout this study and the Biomedical Core Facility of Fudan University for technical support. This work was supported by Ministry of Science and Technology (grant no. 2019YFA0801703), National Natural Science Foundation of China (grant no. 81790250, 81790253 and 91959202) and Innovation Program of Shanghai Municipal Education Commission (no. N173606) to Q.-Y.L. and National Natural Science Foundation of China (grant no. 81872240) to M.Y.

Author information

Affiliations

Authors

Contributions

J.-T.L., M.Y. and D.W. performed the experiments. J.-T.L. and M.Y. analysed the data and co-wrote the manuscript. J.W., M.-Z.L. and Y.Z. performed the immunoprecipitation and immunoblot of TRIM21 and the kinase assay, Y.L., Z.-J.C., S.-W.Z. and D.S. contributed to analysis of the data from human PDAC samples and mouse samples. M.-Z.L, L.Z., H.-J.L. and W.-Y.W. performed liquid chromatography–mass spectrometry and data analysis. L.-P.H. and Z.-G.Z performed the KPC mouse experiment. Y.-P.W. and Z.-J.C. provided intellectual discussion. Q.-Y.L. conceived the idea, designed and supervised the study, analysed the data and co-wrote the manuscript.

Corresponding author

Correspondence to Qun-Ying Lei.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 BCAT2 but not BCAT1 is elevated in PDAC cells.

a, Alteration in amino acids concentrations in pancreatic tissue of KC mice at the age of 2 months (mean ± s.e.m. of n = 6 biologically independent animals, two-tailed t-test). b, Increased BCAT2 protein level in PDAC cells, by comparing to slight difference of BCAT1 expression (data are representative of three biologically independent experiments). c-e, Representative images of Bcat1 and Bcat2 staining of pancreatic tissue specimens from Control (Con) (n = 20 biologically independent animals), KC (n = 20 biologically independent animals), and KPC (n = 10) mice and human PDAC (n = 72 biologically independent patients). f. Representative images and quantification of Pi-Bckdha, Bckdha, Hmgcl, Acadm, Hadh in KC mice (mean ± s.e.m. of n = 6 biologically independent animals, median indicated as dotted lines, two-tailed t-test). Pancreatic acinar, islet, normal pancreatic duct, PanIN duct, and PDAC area were indicated as asterisk, rhombus, arrowhead, arrow, and dotted arrow, respectively. Scale bar: c, d, e: 12.5 μm; f: 50 μm. Source data

Extended Data Fig. 2 Bcat2 knockout impedes PDAC development at early stage.

a, b, Bcat1 has no functional compensation in KC;Bcat2-/- mice (n = 6 biologically independent animals). Representative images of Bcat1(a) and Bcat2 (b) staining. c-g, Representative images of staining with alcian blue (c), sirius red (d), and a serial section of Bcat2 (e), Ki67 (f) and CK19 (g) of pancreatic tissues from KC, KC;Bcat2+/- or KC; Bcat2-/- mice (6 months, n = 6 biologically independent animals, pancreatic acinar and duct indicated as arrow or asterisk, respectively, scale bar: c,d: 50 μm; a,b,e,f,g: 12.5 μm).

Extended Data Fig. 3 Extended Data Fig. 3 BCAT2 is essential for PDAC.

a, b, Establishment of BCAT2 overexpression in H6C7 and HPNE cells (a) and BCAT2 knockdown in SW1990 and BxPC3 cells (b), data are representative of three biologically independent experiments. c, d, BCAA consumption is increased in BCAT2-overexpressing H6C7 and HPNE cells (c) and decreased in BCAT2 silencing SW1990 and BxPC3 cells (d) (mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test). e-h, Increased colony formation (e, f) and cell migration (g, h) in BCAT2-overexpressing H6C7 and HPNE cells (mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test, scale bar: 200 μm). i-l, Decreased colony formation (i, j) and cell migration (k, l) in BCAT2-silencing SW1990 and BxPC3 cells (mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test, scale bar: 200 μm). m-r, Bcat2 knockdown does not affect tumor formation but suppresses growth of Panc02 cells transplanted orthotopically in C57BL/6 J mice (n = 10 biologically independent animals per group). Establishment of Panc02 cells with Bcat2 knockdown using dox-induced shRNA targeting Bcat2 (m, data are representative of three biologically independent experiments), photo of orthotopical transplantation in nude mice (n), distributions of pancreas weight (o, mean ± s.e.m. of n = 10 biologically independent animals, two-tailed t-test), representative images of H&E (p, n = 10 biologically independent animals)- and Ki67 (r, n = 10 biologically independent animals)-staining of transplanted tumor specimen, and quantification of tumor formation (q, n = 10 biologically independent animals) and Ki67 positive cells (s, each 10 fields, mean ± s.e.m., two-tailed t-test) (Scale bar: 12.5 μm). Source data

Extended Data Fig. 4 BCAT2-mediated BCAA catabolism is essential for PDAC.

a, Establishment of PANC1 cells with stable BCAT2 knockdown (data are representative of three biologically independent experiments). b-h, Quantification of metabolites abundance in SW1990 (b, e, f, mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test) and PANC1 (c, e, g, mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test) cells with or without BCAT2 silencing and pancreatic duct organoids from KC or KC;Bcat2-/- mice (d,e,h, mean ± s.e.m. of n = 4 biologically independent experiments (d, h), n = 3 biologically independent experiments (e), two-tailed t-test). i. Establishment of BCAT2 WT or Y229A put back in SW1990 cells. Data are representative of three biologically independent experiments. j-n, BCAT2 WT but not Y229A put back recovers mitochondrial potential (j, mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test), mitochondrial ROS (k, mean ± s.e.m. of n = 5 biologically independent experiments, two-tailed t-test), OCR (l, mean ± s.e.m. of n = 6 biologically independent experiments, two-tailed t-test), ECAR (m, mean ± s.e.m. of n = 6 biologically independent experiments, two-tailed t-test) and cell proliferation (n, mean ± s.e.m. of n = 4 biologically independent experiments, ***p < 0.001, n.s. donates for no significance, detailed p value is available in Supplementary Table 3, two-tailed t-test). o, Establishment of KRASG12V-overexpressing H6C7 cells and KRAS-silencing PANC1 cells (data are representative of three biologically independent experiments). p, q, KC mice pancreatic ductal organoids growth in presence of BCAT2 inhibitors (20 μM, dissolved in DMSO) in combination with NBs (nucleobases, 250 μM, dissolved in DMSO) and BCKA (150 μM) (p) or BCAA at different concentrations (q) (each 4 fields, scale bar: 200 μm). Source data

Extended Data Fig. 5 KRAS stabilizes BCAT2 mediated by E3 ligase TRIM21.

a, Representative images of BCAT2 staining in adjacent pancreatic tissues or PDAC specimens with KRASWT (n = 9 biologically independent patients) or KRASMut (n = 13 biologically independent patients) (Scale bar: 12.5 μm). b, No effect on BCAT2 mRNA expression by KRAS overexpression in H6C7 cells or KRAS knockdown in SW1990 cells (mean ± s.e.m. of n = 3 biologically independent experiments, two-tailed t-test). c, KRASG12V stabilizes BCAT2 protein level in H6C7 cells analyzed by CHX treatment (two-tailed t-test). d, TRIM21 knockdown decreases BCAT2 ubiquitylation. Data are representative of three biologically independent experiments in c and d. Source data

Extended Data Fig. 6 BCAT2 is phosphorylated at Y228 site.

a, Attenuation of BCAT2 ubiquitylation by KRAS and/or BCAT2Y228F mutant. b, Disruption of semi-endogenous interaction between BCAT2 and TRIM21 by BCAT2Y228F mutant. c, d, Y228F mutant stabilizes BCAT2 protein level analyzed by CHX treatment (d, mean ± s.e.m. of n = 3 biologically independent experiments, *p < 0.05, detailed p value is available in Supplementary Table 3, two-tailed t-test). e, BCAT2Y228F mutant decreases tyrosine phosphorylation of BCAT2 detected by pan-tyrosine phosphorylation antibody. f, Anti-phospho-BCAT2 (Y228) antibody specifically recognizes site-specific (Y228) phosphopeptide of BCAT2 immobilized on NC membrane. g, Site-specific (Y228) phosphopeptide of BCAT2 prevents recognition of anti-phospho-BCAT2 (Y228) antibody to BCAT2-WT. h, BCAT2Y228F mutant decreases phosphorylation of BCAT2 at tyrosine residue (Y228) detected by using anti-phospho-BCAT2 (Y228) immune serum. Pre-immune serum as negative control. Data are representative of three biologically independent experiments in a, b, c, e, f, g and h. Source data

Extended Data Fig. 7 Kinase SYK phosphorylates BCAT2 at Y228 site.

a, Identification of SYK as tyrosine kinase for BCAT2 phosphorylation at 228 tyrosine residue (Y228) using tyrosine kinase library screening. b, Y228F mutant decreases SYK-mediated phosphorylation of BCAT2. c, Enhanced ubiquitylation of BCAT2WT, but not BCAT2Y228 mutant by SYK in HEK293T cells. d, Representative images SYK- and BCAT2-staining of serial sections from adjacent tissues and PDAC specimens (n = 22 biologically independent patients, acinar, adjacent duct, PDAC area and stroma cells were indicated as asterisk, arrowhead, arrow and dotted arrow, respectively. Scale bar: 12.5 μm). Data are representative of three biologically independent experiments in a, b and c. Source data

Extended Data Fig. 8 Bcat2 inhibitor impedes PDAC development.

a-f, Alleviation of PanIN progression by Bcat2 inhibitor in KC mice at late stage. Representative images and quantification of alcian blue (a, n = 5 biologically independent animals per group, b, each 5 fields, mean ± s.e.m., two-tailed t-test)-, sirius red (c, n = 5 per group biologically independent animals, d, each 5 fields, mean ± s.e.m., two-tailed t-test)-, Ki67 (e, n = 5 biologically independent animals per group, f, each 10 fields, mean ± s.e.m., two-tailed t-test)-, and CK19 (g, n = 5 biologically independent animals per group)-staining (scale bars: a, c: 50 μm; e, g: 12.5 μm). h, i, No significant change of food intake (h, mean ± s.e.m. of n = 7 biologically independent samples, two-tailed t-test) and body weight (i, mean ± s.e.m. of n = 5 biologically independent animals) of Control (Con) and KC mice by Bcat2 inhibitor treatment. j, k No effect on glucose homeostasis in Con and KC mice with Bcat2 inhibitor treatment. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were analyzed (mean ± s.e.m. of n = 5 biologically independent animals, n.s. donates for no significance, detailed p value is available in Supplementary Table 3, two-tailed t-test). Source data

Extended Data Fig. 9 Low-BCAA diet impedes PDAC development in KC mice.

a, Decreased plasma BCAA concentration in mice fed on low-BCAA diet (mean ± s.e.m. of n = 8 biologically independent animals, two-tailed t-test). b,c, Significantly decreased pancreas weight of mice at the age of 4 (b, mean ± s.e.m. of n = 7 biologically independent animals, two-tailed t-test) and 6 (c, mean ± s.e.m. of n = 6 biologically independent animals, two-tailed t-test) months by feeding with low-BCAA diet. d-f, Impeded PanIN lesions of KC mice at the age of 2, 4, and 6 months by low-BCAA diet. Representative images (d, data are representative of three biologically independent experiments) and quantification of alcian blue (e, each 7 fields, mean ± s.e.m., two-tailed t-test)- and sirius red (f, each 7 fields, mean ± s.e.m., two-tailed t-test)-staining (scale bars: 50 μm). g-h, Suppression of pancreatic duct cell growth in PanIN lesions of KC mice by low-BCAA diet. Representative images (g, data are representative of three biologically independent experiments) and quantification of Ki67 (h, each 10 fields, mean ± s.e.m., two-tailed t-test)- and CK19-staining (scale bars: 12.5 μm). i, No significant change of food intake, of Control (Con) and KC mice fed with normal or low-BCAA diet (mean ± s.e.m. of n = 8 biologically independent samples, two-tailed t-test). j, Low-BCAA diet results in decreased body weight in both Con and KC mice (mean ± s.e.m. of n = 8 biologically independent animals, ***p < 0.001, detailed p value is available in Supplementary Table 3). k, l, No significant effect on glucose homeostasis of KC mice by low-BCAA diet. GTT and ITT were analyzed (mean ± s.e.m. of n = 4 biologically independent animals (k), n = 5 biologically independent animals (l), n.s. donates for no significance, detailed p value is available in Supplementary Table 3, two-tailed t-test). m, Low-BCAA diet decreases density of skeletal muscle. Representative images of H&E staining for different organs harvested at the age of 4 month (n = 5 biologically independent animals per group, scale bars: 50 μm). Source data

Extended Data Fig. 10 Low-BCAA diet impedes PDAC development in KPC mice.

a, Low-BCAA diet suppresses PDAC progress in KPC mice. Representative images Ki67- and CK19-staining of PDAC specimens from KPC mice (n = 5 biologically independent animals, scale bars: 12.5 μm). b, c, No significant effect on glucose homeostasis of KPC mice by low-BCAA diet. GTT and ITT were analyzed (mean ± s.e.m. of n = 5 biologically independent animals, n.s. donates for no significance, detailed p value is available in Supplementary Table 3, two-tailed t-test). Source data

Supplementary information

Reporting Summary

Supplementary Tables

Clinical information of PDAC patients, TAP-MS of BCAT2 and detailed P values for related figures.

Source data

Statistical Source Data Fig. 1

Statistical Source Data

Statistical Source Data Fig. 2

Statistical Source Data

Statistical Source Data Fig. 3

Statistical Source Data

Unprocessed Blots Figure 3

Unprocessed Western Blots

Statistical Source Data Fig. 4

Statistical Source Data

Unprocessed Blots Figure 4

Unprocessed Western Blots

Statistical Source Data Fig. 5

Statistical Source Data

Statistical Source Data Extended Data Fig. 1

Statistical Source Data

Unprocessed Blots Extended Data Fig. 1

Unprocessed Western Blots

Statistical source Data Extended Data Fig. 3

Statistical Source Data

Unprocessed Blots Extended Data Fig. 3

Unprocessed Western Blots

Statistical source Data Extended Data Fig. 4

Statistical Source Data

Unprocessed Blots Extended Data Fig. 4

Unprocessed Western Blots

Statistical source Data Extended Data Fig. 5

Statistical Source Data

Unprocessed Blots Extended Data Fig. 5

Unprocessed Western Blots

Statistical source Data Extended Data Fig. 6

Statistical Source Data

Unprocessed Blots Extended Data Fig. 6

Unprocessed Western Blots

Unprocessed Blots Extended Data Fig. 7

Unprocessed Western Blots

Statistical source Data Extended Data Fig. 8

Statistical Source Data

Statistical source Data Extended Data Fig. 9

Statistical Source Data

Statistical source Data Extended Data Fig. 10

Statistical Source Data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, JT., Yin, M., Wang, D. et al. BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma. Nat Cell Biol 22, 167–174 (2020). https://doi.org/10.1038/s41556-019-0455-6

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing