Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

doi:10.1016/j.cmet.2019.01.002

. 2019 May 7;29(5):1135-1150.e6.

doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31.

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

Adeola O Adebayo Michael¹, Sungjin Ko¹, Junyan Tao¹, Akshata Moghe², Hong Yang³, Meng Xu⁴, Jacquelyn O Russell¹, Tirthadipa Pradhan-Sundd¹, Silvia Liu¹, Sucha Singh¹, Minakshi Poddar¹, Jayvir S Monga⁵, Pin Liu⁶, Michael Oertel¹, Sarangarajan Ranganathan⁷, Aatur Singhi⁸, Sandra Rebouissou⁹, Jessica Zucman-Rossi⁹, Silvia Ribback¹⁰, Diego Calvisi¹⁰, Natalia Qvartskhava¹¹, Boris Görg¹¹, Dieter Häussinger¹¹, Xin Chen¹², Satdarshan P Monga¹³

Affiliations

¹ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
⁴ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA.
⁵ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁶ Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China.
⁷ Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁹ Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris 75010, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, 75010 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France; Université Paris Diderot, IUH, 75010 Paris, France.
¹⁰ Institute of Pathology, University of Greifswald, Greifswald, Germany.
¹¹ Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹² Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA.
¹³ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: smonga@pitt.edu.

PMID: 30713111
PMCID: PMC6506359
DOI: 10.1016/j.cmet.2019.01.002

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

Adeola O Adebayo Michael et al. Cell Metab. 2019.

. 2019 May 7;29(5):1135-1150.e6.

doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31.

Authors

Affiliations

¹ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
³ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
⁴ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA.
⁵ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁶ Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China.
⁷ Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸ Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁹ Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris 75010, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, 75010 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France; Université Paris Diderot, IUH, 75010 Paris, France.
¹⁰ Institute of Pathology, University of Greifswald, Greifswald, Germany.
¹¹ Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹² Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA.
¹³ Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: smonga@pitt.edu.

PMID: 30713111
PMCID: PMC6506359
DOI: 10.1016/j.cmet.2019.01.002

Abstract

Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.

Keywords: Wnt; beta-catenin; glutamine synthetase; hepatocellular cancer; liver tumor; mTOR; metabolic zonation; personalized medicine; precision therapy; tumor metabolism.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests

Dr. Monga had grant funding and was a consultant for Abbvie and Dicerna but has no competing financial interests directly relevant to the current study. None of the other authors have any relevant competing interests to declare.

Figures

**Figure 1.. Mouse models of HCC with CTNNB1 mutations display simultaneous positivity for GS and p-mTOR-S2448.**
A. IHC on serial liver sections shows same tumor foci to be positive for GS and p-mTOR-S2448 in the Met-β-catenin, Kras-β-catenin and Nrf2-β-catenin models (50×). Cholangiocarcinoma (CCA) occurring in Kras-β-catenin model are negative. IHC on serial sections also shows hepatoblastoma (HB) to be positive for GS and p-mTOR-S2448 in Yap-β-catenin model (50×). B. IHC on serial liver sections shows same tumor foci to be negative for GS and p-mTOR-S2448 in the Met-WT-β-catenin HCC model generated by co-expressing wild-type non-mutant β-catenin and c-Met (50×).

**Figure 2:. Human liver tumors with *CTNNB1* mutations and/or GS upregulation show significant increase in p-mTOR-S2448**
A. Levels of p-mTOR-S2448 were dramatically increased in *CTNNB1*-mutated HCA (blue) as compared to adjacent non-tumor livers (gray) and *CTNNB1* non-mutated HCA (red) by WB. Ponceau staining confirmed comparable protein loading. *GLUL* mRNA expression was assessed by qRT-PCR and showed increased expression in *CTNNB1*-mutated HCA with different mutations/deletions in *CTNNB1* noted with different colors. B. For each sample, expression level of each protein was quantified using Image Lab software (Bio-Rad). Kruskall-Wallis and Mann-Whitney test were used to assess differences between groups and showed significant increase in p-mTOR-S2448 in *CTNNB1*-mutated HCA as compared to other groups (****p=0.0002). C. 32% (n=37) of all HCC cases (n=116) at the University of Greifswald cohort were simultaneously positive for GS and p-mTOR-S2448. Bar graph representing Fisher’s exact test showed a significant correlation between GS and p-mTOR-S2448 staining in these samples (****p=2.34E-19; 2-sided test). D. 16% (n=40) of the 252 usable cases represented on 6 TMAs representing the UPMC cohort, were simultaneously positive for GS and p-mTOR-S2448 while 169 cases were negative for both these markers. Fisher’s exact test showed a significant correlation between GS and p-mTOR-S2448 (****p=4.26E-17, 2-sided test). E. Representative IHC of HCC samples from the University of Greifswald cohort showing simultaneous positivity (Patient A) or negativity (Patient B) for GS and p-mTOR-S2448 (50×). F. Representative IHC of HCC samples from the UPMC cohort TMA showing simultaneous positivity (Patient C) for GS and p-mTOR-S2448 (100×). See also Figures S1, S2, S3 and S7 and Tables S1, S2 and S3.

**Figure 3:. Pericentral expression of GS and p-mTOR-S2448 in normal human and mouse liver is β-catenin-dependent.**
A. Serial sections from a normal human (top) and mouse (bottom) liver stained for GS and p-mTOR-S2448 show positive staining for both only in the zone 3 hepatocytes (50×). B. Representative IHC shows staining in zone-3 hepatocytes of GS and p-mTOR-S2448 in β-catenin^fl/fl mice (top), which was absent in Alb-Cre/β-catenin^fl/fl (bottom) (100×). See also Figures S4 and S7

**Figure 4:. Pericentral expression of p-mTOR-S2448 is the function of GS and in turn Glutamine, downstream of the Wnt-β-catenin pathway.**
A. Conditional deletion of Glul in Alb-Cre/GS^fl/fl mice leads to loss of GS and p-mTOR-S2448 in zone-3 hepatocytes (bottom), which was intact in GS^fl/fl littermates (top) (100×). B. Double immunofluorescence validates colocalization of GS and p-mTOR-S2448 in the zone-3 hepatocytes in GS^fl/fl mice (top), while no staining for either was seen in the liver sections from Alb-Cre/GS^fl/fl mice (bottom) (200×). C. IHC on serial sections from livers of Alb-Cre/β-catenin^fl/fl mice following forced expression of S45Y-*CTNNB1* by SB-HTVI in a subset of zone-3 hepatocytes shows ectopic expression of β-catenin, GS and p-mTOR-S2448 in the same hepatocytes (100×). D. IHC on serial sections from livers of Alb-Cre/GS^fl/fl mice following forced expression of *GLUL* by SB-HTVI in a subset of zone-3 hepatocytes shows ectopic expression of GS and p-mTOR-S2448 in the same hepatocytes (100×). E. GS was silenced in Hep3B cells using validated siRNA against *GLUL* as compared to siRNA against non-specific scrambled sequence for 24 hours, followed by supplementation with 4mM of Glutamine for another 24 hours. WB shows that *GLUL* siRNA successfully decreased GS as well as p-mTOR-S2448, which was restored by Glutamine supplementation. Equivalent protein loading was confirmed by GAPDH. Densitometry analysis (color-coded) on normalized sampled showed Glutamine supplementation dramatically increasing p-mTOR-S2448 after GS knockdown. See also Figure S5.

**Figure 5:. Increased glutamine levels in β-catenin mutant HCC makes them susceptible to mTORC1 loss or inhibition alone or in combination with GC1.**
A. Significantly higher glutamine levels were observed in the tumor bearing livers from the S45Y-CTNNB1-Met, S45Y-CTNNB1-G12D-Kras and S45Y-CTNNB1-S127A-Yap models as compared to normal FVB livers. (**p<0.01) B. Gross (top) and H&E staining from the representative livers (bottom) from the Raptor^fl/fl mice injected for 6.7 weeks with the Met-β-catenin-pCMV or Raptor^fl/fl mice injected for 6.7 or 17.1 weeks with the Met-β-catenin-pCMV-Cre. Macroscopic and microscopic HCC is visible in the pCMV but not in pCMV-Cre group. (100×; scale bar=200μm) C. 3D-US identified focal round lesions that were both hypo-echoic and hyper-echoic in the basal diet control group, which were notably decreased in the Rapamycin only group, with even a more profound decrease in the Rapamycin+GC1 group. Gross images of livers in mice confirmed the relative decrease in disease in Rapamycin only and complete absence of disease in combination group as compared to the control. D. Significant decrease in tumor volume calculated based on 3D-US was evident in both Rapamycin and Rapamycin+GC1 group as compared to basal diet (**p<0.01). E. Significant decrease in the liver weight to body weight ratio (LW/BW), an indicator of tumor burden was observed after treatment for 5 weeks with either Rapamycin alone (*p<0.05) or Rapamycin+GC1 (***p<0.005) See also Figures S6 and S7.

**Figure 6.. Decreased tumor burden seen by macroscopic and histological analysis after 5 weeks of mTORC1 Inhibition alone but more profoundly in combination with GC1.**
A. Gross images of individual representative livers from the 3 groups showing decreased macroscopic tumor burden in Rapamycin alone and more so in the Rapamycin+GC1 group as compared to the controls. B. H&E staining and IHC for GS and p-mTOR-S2448 on serial sections shows large tumor foci staining positive for the two markers in basal diet group and notably smaller nodules in Rapamycin treatment only (50×). C. H&E staining and IHC for GS and p-mTOR-S2448 on serial sections shows large tumor foci staining positive for the two markers in basal diet group and lack of any nodules in the Rapamycin+GC1 treatment with normal zonated appearance for the two markers (50×). See also Figure S6.

**Figure 7.. Five-week treatment with Rapamycin+GC1 combats Met-β-catenin HCC and is superior to treatment with Rapamycin alone.**
A. IHC for Myc tag representing mutant-β-catenin and V5-tag representing c-Met, shows all tumors in basal diet group to be positive and thus derived from the injected plasmids. A notable decrease in IHC for both markers indicates a complete response to the combination therapy (50×). B. A representative tiled image from IHC for Myc-tag from the basal diet-fed versus Rapamycin+GC1 diet-fed Met-β-catenin mice shows a dramatic difference in overall histologic tumor burden which was also confirmed by WB for Myc-tag. GAPDH confirmed equal loading. C. IHC for p-S6-S235/236 and p-S6-240/244, indicators of mTORC1 activity, showed notably smaller positive nodules in the combination treatment as compared to basal diet in the Met-β-catenin model (50×). D. Decreased number of tumor cells were PCNA-positive in the Rapamycin+GC1 group versus basal diet (100×), and increased number of TUNEL-positive cells were evident in the combination treatment than controls (100×). E. Representative WB using lysates from tumor-bearing livers from Met-p-catenin HCC model comparing Met signaling in controls versus Rapamycin alone and controls versus Rapamycin+GC1. P-Met- and p-Stat3 were comparably downregulated in both treatment groups as compared to the controls, however p-Erk1/2 was decreased in only the Rapamycin+GC1 group. GAPDH verified comparable loading in both sets of analyses. See also Figure S6.

**Figure 8.. Two-week treatment of Met-β-catenin mice with Rapamycin+GC1 impacts mTORC1 and p-Erk signaling to reduce proliferation and increase cell death, to eventually affect HCC burden profoundly.**
A. LW/BW was compared between controls and Rapamycin+GC1 group at 2, 4 and 5 weeks after intervention. Progressive increase in tumor burden was evident in controls but not in the combination treatment group. At 2 weeks of treatment, there was insignificant difference in LW/BW in the treatment group and controls (*p<0.05). B. IHC for Myc-tag showed isolated cells or small clusters representing small tumor foci in the control and Rapamycin+GC1-treated Met-β-catenin mice at 2 weeks with marginally fewer and smaller foci seen in the treatment group (50×). C. A notable decrease in the number of PCNA-positive tumor cells and an increase in the numbers of TUNEL-positive nuclei is evident in the Rapamycin+GC1 group as compared to basal diet fed controls at 2 weeks. D. WB using liver lysates from Met-β-catenin mice on basal diet or Rapamycin+GC1 diet for 2 weeks show a notable decrease in p-S6-S235/236, p-S6-240/244, total 4EBP1 and p-4EBP1-T37/46 as well as p-Erk-T202/Y204 which was quantified and presented as bar graph (lower panel). WB for GAPDH depicts comparable protein loading. E. Representative IHC shows a notable decrease in staining for p-mTOR-S2448 and pS6-S240/244 in 2-week Rapamycin+GC1 treatment versus controls.

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Comment in

Position Is Destiny: Metabolism and Cell Identity.
Goessling W. Goessling W. Cell Metab. 2019 May 7;29(5):1017-1019. doi: 10.1016/j.cmet.2019.04.008. Cell Metab. 2019. PMID: 31067445 Free PMC article.
Mammalian Target of Rapamycin Inhibitors, New Drugs for Beta-Catenin-Mutated Hepatocellular Carcinomas?
Perret C, Decaens T. Perret C, et al. Hepatology. 2019 Oct;70(4):1473-1476. doi: 10.1002/hep.30768. Epub 2019 May 16. Hepatology. 2019. PMID: 31095753 No abstract available.

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References

1. Altman BJ, Stine ZE, and Dang CV (2016). From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16, 749. - PubMed
1. Behari J, Li H, Liu S, Stefanovic-Racic M, Alonso L, O’Donnell CP, Shiva S, Singamsetty S, Watanabe Y, Singh VP, et al. (2014). beta-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. Am J Pathol 184, 3284–3298. - PMC - PubMed
1. Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, Vasseur-Cognet M, Kuo CJ, Kahn A, Perret C, et al. (2006). Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10, 759–770. - PubMed
1. Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, Kitajewski J, Kahn A, and Perret C (2002). New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21, 8293–8301. - PubMed
1. Chafey P, Finzi L, Boisgard R, Cauzac M, Clary G, Broussard C, Pegorier JP, Guillonneau F, Mayeux P, Camoin L, et al. (2009). Proteomic analysis of beta-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway. Proteomics 9, 3889–3900. - PubMed

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[1] Altman BJ, Stine ZE, and Dang CV (2016). From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16, 749. - PubMed

[2] Altman BJ, Stine ZE, and Dang CV (2016). From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16, 749. - PubMed

[3] Behari J, Li H, Liu S, Stefanovic-Racic M, Alonso L, O’Donnell CP, Shiva S, Singamsetty S, Watanabe Y, Singh VP, et al. (2014). beta-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. Am J Pathol 184, 3284–3298. - PMC - PubMed

[4] Behari J, Li H, Liu S, Stefanovic-Racic M, Alonso L, O’Donnell CP, Shiva S, Singamsetty S, Watanabe Y, Singh VP, et al. (2014). beta-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. Am J Pathol 184, 3284–3298. - PMC - PubMed

[5] Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, Vasseur-Cognet M, Kuo CJ, Kahn A, Perret C, et al. (2006). Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10, 759–770. - PubMed

[6] Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, Vasseur-Cognet M, Kuo CJ, Kahn A, Perret C, et al. (2006). Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10, 759–770. - PubMed

[7] Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, Kitajewski J, Kahn A, and Perret C (2002). New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21, 8293–8301. - PubMed

[8] Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, Kitajewski J, Kahn A, and Perret C (2002). New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21, 8293–8301. - PubMed

[9] Chafey P, Finzi L, Boisgard R, Cauzac M, Clary G, Broussard C, Pegorier JP, Guillonneau F, Mayeux P, Camoin L, et al. (2009). Proteomic analysis of beta-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway. Proteomics 9, 3889–3900. - PubMed

[10] Chafey P, Finzi L, Boisgard R, Cauzac M, Clary G, Broussard C, Pegorier JP, Guillonneau F, Mayeux P, Camoin L, et al. (2009). Proteomic analysis of beta-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway. Proteomics 9, 3889–3900. - PubMed

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Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

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Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

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