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Pathology & Laboratory Medicine

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Metabolic and Signaling Vulnerabilities in Prostate Cancer

Maria T. Diaz-Meco, PhD, Principal Investigator

The focus of the Diaz-Meco laboratory is the study of the molecular and cellular mechanisms that control tumor initiation and progression, and therapy resistance, with a particular interest in the control of lineage plasticity in prostate cancer. The approach of this laboratory is to identify metabolic and epigenetic vulnerabilities that will serve as therapeutic targets for new anti-cancer medicines that would selectively impact the growth and survival of the tumor cell, irrespective of its oncogenic load. The Diaz-Meco lab has recently identified the metabolic pathways underlying the acquisition of therapy-resistance in patients of the most aggressive form of metastatic prostate cancer. These studies unraveled potential therapeutic targets in the control of the metabolic and epigenetic programs whose therapeutic manipulation could restore sensitivity to androgen-deprivation therapy to patients that have become refractory to this type of treatment. The laboratory also studies the metabolic impact that reprogramming of the stroma has on prostate cancer cells and how that crosstalk is regulated during tumor initiation and progression.

Active Projects

  • Epigenetic reprogramming during neuroendocrine differentiation
  • Metabolic control of lineage plasticity by PKCλ⁄ι in neuroendocrine prostate cancer
  • Molecular crosstalk of PKCλ⁄ι with androgen receptor signaling
  • Metabolic vulnerabilities in the tumor microenvironment of prostate cancer
  • Regulation of stromal p62 by tumor epithelial cells in prostate cancer

Active Grants

  • R01CA246765
    NIH/NCI 
    Novel pathways in the control of lineage plasticity in neuroendocrine prostate cancer
    The scope of this study is to investigate the role and mechanism of action of PKCλ⁄ι to orchestrate serine metabolism and epigenetic regulation in NEPC, and to identify novel vulnerabilities that can be exploited therapeutically for its treatment.
    Role: Principal Investigator
  • R01CA192642
    NIH/NCI
    The p62/MEKK3 complex in mTORC1 activation
    The goal of this project is to understand how cells translate nutrient-sensing signals to mTORC1, a critical event in prostate cancer progression.
    Role: Principal Investigator
  • R01CA218254
    NIH/NCI
    Role of p62 in metabolic reprogramming of the tumor stroma in prostate cancer
    The proposed study will provide a detailed understanding of the mechanisms whereby the stromal compartment generates a metabolic microenvironment more resistant to nutrient stress in prostate cancer  
    Role: Principal Investigator
  • R01CA207177
    NIH/NCI
    Mechanisms of cell death and autophagy in intestinal epithelial cells in inflammation and cancers
    The scope of this study is to investigate the role and mechanism of action of PKCλ⁄ι as an essential regulator of autophagy and cell death in intestinal cell homeostasis and inflammation-driven tumorigenesis.
    Role: Co-Investigator
  • 16X113-PHGDH
    NCI-NeXT Program
    PHGDH Inhibitors
    The scope of the proposed project is to identify inhibitors of PHGDH, a cancer metabolism target.
    Role: Co-Investigator
  • RCA 19-02
    Halozyme, Inc
    Characterizing the Effects of PVHA Hyaluronidase in a novel Mouse Model of Colorectal Cancer
    The scope is to test the effect of PVHA in serrated tumors.
    Role: Co-Investigator

Selected Publications

The complexity of the serine glycine one-carbon pathway in cancer.

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

The complexity of the serine glycine one-carbon pathway in cancer.

J Cell Biol. 2020 Jan 6;219(1).

Reina-Campos M, Diaz-Meco MT, Moscat J.

PMID: 31690618

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The Dual Roles of the Atypical Protein Kinase Cs in Cancer

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

The Dual Roles of the Atypical Protein Kinase Cs in Cancer

Cancer Cell. 2019 Sep 16;36(3):218-235. 

Reina-Campos M, Diaz-Meco MT, Moscat J.

PMID: 31474570; PMCID: PMC6751000

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Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.

Maria Teresa Diaz-Meco Conde, PhD

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.

Cancer Cell. 2019 Mar 18;35(3):385-400.

Reina-Campos M, Linares JF, Duran A, Cordes T, L'Hermitte A, Badur MG, Bhangoo MS, Thorson PK, Richards A, Rooslid T, Garcia-Olmo DC, Nam-Cha SY, Salinas-Sanchez AS, Eng K, Beltran H, Scott DA, Metallo CM, Moscat J, Diaz-Meco MT.

PMID: 30827887; PMCID: PMC6424636

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Metabolic reprogramming of the tumor microenvironment by p62 and its partners

Maria Teresa Diaz-Meco Conde, PhD

Metabolic reprogramming of the tumor microenvironment by p62 and its partners

Biochim Biophys Acta Rev Cancer. 2018 Aug;1870(1):88-95.

Reina-Campos M, Shelton PM, Diaz-Meco MT, Moscat J.

PMID: 29702207; PMCID: PMC6193563

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Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor

Cancer Cell. 2018 Apr 9;33(4):770-784.

Huang J, Duran A, Reina-Campos M, Valencia T, Castilla EA, Müller TD, Tschöp MH, Moscat J, Diaz-Meco MT.

PMID: 29634950; PMCID: PMC5896786

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ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma

Cell Metab. 2017 Dec 5;26(6):817-829.

Linares JF, Cordes T, Duran A, Reina-Campos M, Valencia T, Ahn CS, Castilla EA, Moscat J, Metallo CM, Diaz-Meco MT.

PMID: 28988820; PMCID: PMC5718961

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Metabolism shapes the tumor microenvironment

Maria Teresa Diaz-Meco Conde, PhD

Metabolism shapes the tumor microenvironment

Curr Opin Cell Biol. 2017 Oct;48:47-53. 

Reina-Campos M, Moscat J, Diaz-Meco M.

PMID: 28605656; PMCID: PMC5650101

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p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer

Cancer Cell. 2016 Oct 10;30(4):595-609.

Duran A, Hernandez ED, Reina-Campos M, Castilla EA, Subramaniam S, Raghunandan S, Roberts LR, Kisseleva T, Karin M, Diaz-Meco MT, Moscat J.

PMID: 27728806; PMCID: PMC5081228

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p62 in Cancer: Signaling Adaptor Beyond Autophagy

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

p62 in Cancer: Signaling Adaptor Beyond Autophagy

Cell. 2016 Oct 20;167(3):606-609.

Moscat J, Karin M, Diaz-Meco MT.

PMID: 27768885; PMCID: PMC5114003

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p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells

Cancer Cell. 2016 Jun 13;29(6):935-948.

Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M. 

PMID: 27211490; PMCID: PMC4907799

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Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade

Maria Teresa Diaz-Meco Conde, PhD

Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade

Cell Rep. 2015 Aug 25;12(8):1339-52.

Linares JF, Duran A, Reina-Campos M, Aza-Blanc P, Campos A, Moscat J, Diaz-Meco MT.

PMID: 26279575; PMCID: PMC4551582

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Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis

Cancer Cell. 2014 Jul 14;26(1):121-135.

Valencia T, Kim JY, Abu-Baker S, Moscat-Pardos J, Ahn CS, Reina-Campos M, Duran A, Castilla EA, Metallo CM, Diaz-Meco MT, Moscat J.

PMID: 25002027; PMCID: PMC4101061

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K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells

Maria Teresa Diaz-Meco Conde, PhD

K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells

Mol Cell. 2013 Aug 8;51(3):283-96.

Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco MT. 

PMID: 23911927; PMCID: PMC3971544

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c-Myc phosphorylation by PKCζ represses prostate tumorigenesis

Maria Teresa Diaz-Meco Conde, PhD

c-Myc phosphorylation by PKCζ represses prostate tumorigenesis

Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6418-23.

Kim JY, Valencia T, Abu-Baker S, Linares J, Lee SJ, Yajima T, Chen J, Eroshkin A, Castilla EA, Brill LM, Medvedovic M, Leitges M, Moscat J, Diaz-Meco MT.

PMID: 23550155; PMCID: PMC3631641

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Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis

Cell. 2013 Jan 31;152(3):599-611.

Ma L, Tao Y, Duran A, Llado V, Galvez A, Barger JF, Castilla EA, Chen J, Yajima T, Porollo A, Medvedovic M, Brill LM, Plas DR, Riedl SJ, Leitges M, Diaz-Meco MT, Richardson AD, Moscat J. 

PMID: 23374352; PMCID: PMC3963830

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p62: a versatile multitasker takes on cancer

Maria Teresa Diaz-Meco Conde, PhD

p62: a versatile multitasker takes on cancer

Trends Biochem Sci. 2012 Jun;37(6):230-6. 

Moscat J, Diaz-Meco MT.

PMID: 22424619; PMCID: PMC3531712

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Feedback on fat: p62-mTORC1-autophagy connections

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

Feedback on fat: p62-mTORC1-autophagy connections

Cell. 2011 Nov 11;147(4):724-7.

Moscat J, Diaz-Meco MT.

PMID: 22078874; PMCID: PMC3290994

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p62 is a key regulator of nutrient sensing in the mTORC1 pathway

Maria Teresa Diaz-Meco Conde, PhD

p62 is a key regulator of nutrient sensing in the mTORC1 pathway

Mol Cell. 2011 Oct 7;44(1):134-46

Duran A, Amanchy R, Linares JF, Joshi J, Abu-Baker S, Porollo A, Hansen M, Moscat J, Diaz-Meco MT.

PMID: 21981924; PMCID: PMC3190169

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Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma

Maria Teresa Diaz-Meco Conde, PhD

Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma

Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12962-7.

Fernandez-Marcos PJ, Abu-Baker S, Joshi J, Galvez A, Castilla EA, Cañamero M, Collado M, Saez C, Moreno-Bueno G, Palacios J, Leitges M, Serrano M, Moscat J, Diaz-Meco MT.

PMID: 19470463; PMCID: PMC2722271

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p62 at the crossroads of autophagy, apoptosis, and cancer

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

p62 at the crossroads of autophagy, apoptosis, and cancer

Cell. 2009 Jun 12;137(6):1001-4.

Moscat J, Diaz-Meco MT.

PMID: 19524504; PMCID: PMC3971861

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The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis

Cancer Cell. 2008 Apr;13(4):343-54.

Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J.

PMID: 18394557

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Cell signaling and function organized by PB1 domain interactions.

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

Cell signaling and function organized by PB1 domain interactions.

Mol Cell. 2006 Sep 1;23(5):631-40. 

Moscat J, Diaz-Meco MT, Albert A, Campuzano S.

PMID: 16949360

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Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62

Cell Metab. 2006 Mar;3(3):211-22. 

Rodriguez A, Durán A, Selloum M, Champy MF, Diez-Guerra FJ, Flores JM, Serrano M, Auwerx J, Diaz-Meco MT, Moscat J.

PMID: 16517408

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The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis

Dev Cell. 2004 Feb;6(2):303-9.

Durán A, Serrano M, Leitges M, Flores JM, Picard S, Brown JP, Moscat J, Diaz-Meco MT.

PMID: 14960283

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Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62

Maria Teresa Diaz-Meco Conde, PhD

Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62

Mol Cell Biol. 1998 May;18(5):3069-80.

Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT.

PMID: 9566925; PMCID: PMC110686

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The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C

Maria Teresa Diaz-Meco Conde, PhD, Jorge Moscat, PhD

The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C

Cell. 1996 Sep 6;86(5):777-86. 

Díaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J.

PMID: 8797824

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