Enrique Rozengurt, DVM, PhD, AGAF

Signal Transduction GI Cancer / Rozengurt Laboratory


Key investigator

  • Enrique Rozengurt, DVM, PhD, AGAF, FRC Path (UK)

Funding

  • NIH P01CA236585Role: Project Leader; Project 2 Chemoprevention and mechanisms of obesity-promoted pancreatic adenocarcinoma, 05/01/2020 – 04/30/2025
  • NIH R21CA258125 - (MPI: Rozengurt; Eibl) Interaction between chronic stress and obesity in pancreatic cancer progression. 05/01/2022 – 04/30/2024         
  • NIH R21AI156592 - (MPI: Reed, Rozengurt) Targeting YAP with statins to prevent antibody-mediated transplant rejection, 012/18/2020 – 11/30/2023
  • VA Merit Review I01 BX003801 - (PI) Identification of the growth-promoting PKD/YAP axis as a novel target for the statins in intestinal epithelial cells, 07/01/18-06/30/23.
  • Roland Hirshberg Endowed Chair in Translational Pancreatic Cancer Research.

Current research projects

  • KD1 Signaling and Crosstalk Mechanisms in Intestinal Epithelial Cell Regulation
    • Aims: 1) characterize the role of PKD1 signaling in intestinal epithelial cell proliferation in vivo and in stem cell-derived intestinal organoids, 2) characterize crosstalk mechanisms between PKD1 and β-catenin signaling systems in intestinal epithelial cells, and 3) identify a novel mechanism of PKD1 regulation through PAK-mediated PKD1 phosphorylation at the N-terminal residue Ser203.
  • The Hippo/YAP/TAZ Pathway in the Regulation of Intestinal, Pancreatic and Endothelial Cell Proliferation
    • Aims: 1) Characterize the role of the Hippo/YAP/TAZ pathway in the control of proliferation of intestinal and pancreatic epithelial cells, and 2) Identify the signal transduction pathways that mediate the regulation of YAP expression, localization and phosphorylation in these cells.
  • Chemoprevention of Pancreatic Cancer with Anti-Diabetic Agents
    • The aim of this project is to characterize the chemo-preventive effects of metformin on the progression of PanINs using the conditional KrasG12D model subjected to standard or a high fat, high calorie diet (HFCD).  This animal model system recapitulates the lesions seen in the human disease, namely  pancreatic pre-neoplatic lesions followed by their conversion of carcinoma in situ to invasive ductal pancreatic carcinoma.

Future research directions

  • The future directions are an extension of the current research: Signal transduction mechanisms through protein kinase cascades; elucidation of crosstalk mechanism between Protein kinase D (PKD) and downstream gene-regulatory programs; novel approaches in the therapy and prevention of GI cancers, especially pancreatic cancer.

Key publications - Full list on PubMed

  1. Benhammou JN, Qiao B, Ko A, Sinnett-Smith J, Pisegna, Rozengurt ELipophilic statins inhibit YAP co-activator transcriptional activity in HCC cells through Rho-mediated modulation of the actin cytoskeleton. American Journal of Physiology-Gastrointestinal and Liver Physiology. June 27, 2023
  2. Sinnett-Smith J, Torres-Marquez ME, Chang JK, Shimizu Y, Hao F, Martin MG, Rozengurt E. Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids. American Journal of Physiology- Cell Physiology. 324:C807-C820, 2023
  3. Anwar T, Sinnett-Smith J, Jin YP, Reed EF, Rozengurt E. Lipophilic Statins Inhibit YAP Nuclear Localization, Coactivator Activity, and Migration in Response to Ligation of HLA Class I Molecules in Endothelial Cells: Role of YAP Multisite Phosphorylation. Journal of Immunology.  210:1134-1145, 2023
  4. Ako S, Teper Y, Ye L, Sinnett-Smith J, Hines OJ, Rozengurt E, Eibl, G. Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar to Ductal Metaplasia of Pancreatic Cells. Advances in Gastroenterology and Hepatology.1: 640-651, 2022
  5. Jin YP, Nevarez-Mejia J, Terry AQ, Sosa RA, Heidt S, Valenzuela NM, Rozengurt E, Reed EF. Cross-Talk between HLA Class I and TLR4 Mediates P-Selectin Surface Expression and Monocyte Capture to Human Endothelial Cells. Journal of Immunology. 209: 1359-1369, 2022
  6. Sinnett-Smith J, Anwar T, Reed EF, Teper Y, Eibl G, Rozengurt E. Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy. Molecular Cancer Therapeutics. 21: 1652-1662, 2022
  7. Anwar T, Sinnett-Smith J, Jin YP, Reed EF, Rozengurt E. Ligation of HLA Class I Molecules Induces YAP Activation through Src in Human Endothelial Cells. Journal of Immunology. 205:1953-1961, 2020
  8. Chang HH, Moro A, Chou CEN, Dawson DW, French S, Schmidt AI, Sinnett-Smith J, Hao F, Hines OJ, Eibl G, Rozengurt EMetformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse ModelSci Rep, 2018 12; 8(1):5899
  9. Hao F, Xu Q, Zhao Y, Stevens JV, Young SH, Sinnett-Smith J, Rozengurt E. Insulin receptor and GPCR crosstalk stimulates YAP via PI3K and PKD in pancreatic cancer cells. Mol Cancer Res 2017;15: 929-41
  10. Chang JK, Ni Y, Han L, Sinnett-Smith J, Jacamo R, Rey O, Young SH, Rozengurt E. Protein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization. J Biol Chem 2017; 292:9523-39
  11. Wang J, Sinnett-Smith J, Stevens JV, Young SH, Rozengurt E. Biphasic regulation of Yes-associated Protein (YAP) cellular localization, phosphorylation and activity by G protein-coupled receptor agonists in intestinal epithelial cells: a novel role for protein kinase D (PKD). J Biol Chem 2016;291: 17988-18005

Recent Reviews

  1. Rozengurt E, Eibl G. Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug ResistanceCancers 13: 5126, 2021
  2. Eibl G, Rozengurt E. Obesity and Pancreatic Cancer: Insight into MechanismsCancers 13: 5067, 2021

Past GI/STAR research fellows

  • Jihane N. Benhammou, MD, PhD
  • Terence Chiu, MD, PhD
  • Sushovan Guha, MD, PhD
  • J. Adrian Lunn, MD, PhD
  • Heloisa Soares, MD, PhD

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