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.
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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 8–10 are provided with the paper.
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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.
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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.
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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.
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).
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).
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.
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.
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.
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).
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).
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).
Supplementary information
Supplementary Tables
Clinical information of PDAC patients, TAP-MS of BCAT2 and detailed P values for related figures.
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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
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DOI: https://doi.org/10.1038/s41556-019-0455-6
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