Pathology & Laboratory Medicine

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Inflammatory and Metabolic Pathways in Cancer

Jorge Moscat, PhD, Principal Investigator

The signaling pathways that regulate inflammation and cell proliferation, and their interface with autophagy and metabolism, are central to the control of tumor initiation and progression as well as in the development of metastasis. The Moscat laboratory studies these processes in the context of the crosstalk between the tumor epithelium, the tumor stroma, and its immunological microenvironment. Emphasis is placed on colorectal and liver cancer. The lab pays particular attention to the role and mechanism of action of several key signaling molecules, which include the autophagy and signaling adapters p62 and NBR1, and their binding partners, the atypical protein kinase C isoforms PKCζ and PKCλ⁄ι. The study of these fundamental biological questions results in the identification of non-oncogenic vulnerabilities that will lead to the design of more efficacious and less toxic anti-cancer therapies by targeting not only the epithelium but also the tumor stroma.

Active Projects

  • Autophagy and cell survival in intestinal tumorigenesis
  • Stem cell populations and signaling in intestinal inflammation and cancer
  • Stromal activation and immune response in therapy resistance in colorectal cancer
  • Stromal control of the immunological microenvironment in liver cancer
  • Metabolic reprograming and oxidative stress in hepatocellular carcinoma
  • Identification and design of new anti-cancer drugs targeting the serine metabolism

Active Grants

  • R01DK108743
    NIH/NIDDK
    Control of Stellate Cells-Driven Liver Cancer by the p62/NBR1 Adapters
    The goal of this proposal is to investigate the role and mechanisms of action of p62 and NBR1 in the activation of hepatic stellate cells, and their impact during NASH and liver cancer development.  
    Role: Principal Investigator
  • R01CA211794
    NIH/NCI
    Role of p62/SQSTM1 in obesity-induced liver cancer
    This project will address the mechanisms through which p62 drives HCC development, focusing on the roles of NRF2 and mTORC1 as p62 effectors. Small molecules that interfere with p62-driven NRF2 and mTORC1 activation will be developed and evaluated their ability to prevent obesity-induced HCC in appropriate mouse models.
    Role: Principal Investigator
  • R01CA207177
    NIH/NCI
    Mechanisms of cell death and autophagy in intestinal epithelial cells in inflammation and cancer
    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: Principal 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: Principle Investigator
  • RCA 19-02
    Haloyme, 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: Principal 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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Serrated Colorectal Cancer: The Road Less Travelled?

Jorge Moscat, PhD

Serrated Colorectal Cancer: The Road Less Travelled?

Trends Cancer. 2019 Nov;5(11):742-754.

Nakanishi Y, Diaz-Meco MT, Moscat J.

PMID: 31735291; PMCID: PMC6894428

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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

Jorge Moscat, 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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Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance

Jorge Moscat, PhD

Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance

Immunity. 2018 Dec 18;49(6):1132-1147.e7.

Nakanishi Y, Duran A, L'Hermitte A, Shelton PM, Nakanishi N, Reina-Campos M, Huang J, Soldevila F, Baaten BJG, Tauriello DVF, Castilla EA, Bhangoo MS, Bao F, Sigal D, Diaz-Meco MT, Moscat J.

PMID: 30552022; PMCID: PMC6301096

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The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer

Jorge Moscat, PhD

The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer

Cell Rep. 2018 Apr 24;23(4):1178-1191.

Shelton PM, Duran A, Nakanishi Y, Reina-Campos M, Kasashima H, Llado V, Ma L, Campos A, García-Olmo D, García-Arranz M, García-Olmo DC, Olmedillas-López S, Caceres JF, Diaz-Meco MT, Moscat J.

PMID: 29694894; PMCID: PMC5958623

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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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Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Jorge Moscat, PhD

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Cancer Cell. 2017 Dec 11;32(6):824-839.

Todoric J, Antonucci L, Di Caro G, Li N, Wu X, Lytle NK, Dhar D, Banerjee S, Fagman JB, Browne CD, Umemura A, Valasek MA, Kessler H, Tarin D, Goggins M, Reya T, Diaz-Meco M, Moscat J, Karin M.

PMID: 29153842; PMCID: PMC5730340

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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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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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Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι

Jorge Moscat, PhD

Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι

Cell Rep. 2016 Sep 20;16(12):3297-3310

Nakanishi Y, Reina-Campos M, Nakanishi N, Llado V, Elmen L, Peterson S, Campos A, De SK, Leitges M, Ikeuchi H, Pellecchia M, Blumberg RS, Diaz-Meco MT, Moscat J.

PMID: 27653691; PMCID: PMC5043519

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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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Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ

Jorge Moscat, PhD

Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ

Cell Rep. 2015 Feb 10;10(5):740-754.

Llado V, Nakanishi Y, Duran A, Reina-Campos M, Shelton PM, Linares JF, Yajima T, Campos A, Aza-Blanc P, Leitges M, Diaz-Meco MT, Moscat J.

PMID: 25660024; PMCID: PMC4524805.

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A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity

Jorge Moscat, PhD

A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity

Cell Metab. 2014 Sep 2;20(3):499-511.

Hernandez ED, Lee SJ, Kim JY, Duran A, Linares JF, Yajima T, Müller TD, Tschöp MH, Smith SR, Diaz-Meco MT, Moscat J.

PMID: 25043814; PMCID: PMC4156534

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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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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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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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PKCzeta-regulated inflammation in the nonhematopoietic compartment is critical for obesity-induced glucose intolerance

Jorge Moscat, PhD

PKCzeta-regulated inflammation in the nonhematopoietic compartment is critical for obesity-induced glucose intolerance

Cell Metab. 2010 Jul 7;12(1):65-77.

Lee SJ, Kim JY, Nogueiras R, Linares JF, Perez-Tilve D, Jung DY, Ko HJ, Hofmann SM, Drew A, Leitges M, Kim JK, Tschöp MH, Diaz-Meco MT, Moscat J. 

PMID: 20620996; PMCID: PMC2907185

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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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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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Protein kinase C zeta isoform is critical for mitogenic signal transduction

Jorge Moscat, PhD

Protein kinase C zeta isoform is critical for mitogenic signal transduction

Cell. 1993 Aug 13;74(3):555-63.  

Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, Lozano J, Chapkin RS, Moscat J.

PMID: 7688666

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