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Author Notes:

Dr. Changwon Park, 1501 Kings Hwy, Shreveport, LA 71103, USA. Tel: +13186758856, FAX: +1 (318)675-6005. Email: cpar13@lsuhsc.edu

Dr. Kyunghee Choi, Campus Box 8118, 660 S. Euclid Ave. St. Louis, MO, 63110-1093, USA. Tel: +1 3143628716, FAX: +1 314-747-0809. Email: kchoi@wustl.edu

We thank Mikala Egeblad at Cold Spring Harbor Laboratory for the generous gift of the MMTV-PyMT mice. We want to thank our colleagues at Washington University, Kory Lavine for MCEC cells, Andrew Yoo for BJ-5ta cells, Katherine Weilbaecher for PyMT-BO1-GFP-Luc cells, Luis Batista for pCDH-(LB12-FLAG-TERT)-EF1-NEO plasmid. We thank Robert D. Schreiber at Washington University for 1956 sarcoma cells and helpful suggestions with experimental design and data interpretation. We also want to thank Alexander S Krupnick at the University of Virginia for providing LLC-GFP cells. We thank Mike White and the Genome Engineering and iPSC Center (GEIC) at Washington University in St. Louis for the generation of Myct1 KO mice using CRISPR/CAS9 technology. We also thank Washington University Center for Cellular Imaging (WUCCI) and Pathology FACS core for providing access to the light microscopes and FACS facility, respectively. We thank Attila Kovacs and Carla J. Weinheimer of the Mouse Cardiovascular Phenotyping Core at Washington University School of Medicine for the echocardiogram analysis.

Samuel A. Wickline has Equity in Trasir Therapeutics, Inc. Ashraf Ul Kabir and Kyunghee Choi have a patent pending relating to this work (Application Number: 63/093,595; Title: COMPOSITIONS AND METHODS FOR MODULATING MYCT1). All other authors declare that they have no competing interests.

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Research Funding:

This work was supported by the NIH grants R01HL149954 (to K.C.), R01HL55337 (to K.C), R01HL119291 (to C.P), and K08HL135400 (to C.M.H), Children’s Heart Research and Outcomes Center and Children’s Healthcare of Atlanta 00060337 (to C.P.) and Mallinckrodt Challenge Grant (to K.C. and D.H.F.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • RHO GTPASES
  • T-CELLS
  • EXPRESSION
  • CANCER
  • TARGET
  • GENE
  • VEGF
  • IMMUNOSUPPRESSION
  • OPPORTUNITIES
  • REGENERATION

Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity

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Journal Title:

SCIENCE TRANSLATIONAL MEDICINE

Volume:

Volume 13, Number 583

Publisher:

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The cross-talk between angiogenesis and immunity within the tumor microenvironment (TME) is critical for tumor prognosis. While pro-angiogenic and immunosuppressive TME promote tumor growth, anti-angiogenic and immune stimulatory TME inhibit tumor progression. Therefore, there is a great interest in achieving vascular normalization to improve drug delivery and enhance antitumor immunity. However, anti–vascular endothelial growth factor (VEGF) mechanisms to normalize tumor vessels have offered limited therapeutic efficacies for patients with cancer. Here, we report that Myct1, a direct target of ETV2, was nearly exclusively expressed in endothelial cells. In preclinical mouse tumor models, Myct1 deficiency reduced angiogenesis, enhanced high endothelial venule formation, and promoted antitumor immunity, leading to restricted tumor progression. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed a significant (P < 0.05) correlation between MYCT1 expression, angiogenesis, and antitumor immunity in human cancers, as suggested by decreased FOXP3 expression and increased antitumor macrophages in patients with low MYCT1 expression. Mechanistically, MYCT1 interacted with tight junction protein Zona Occludens 1 and regulated Rho GTPase-mediated actin cytoskeleton dynamics, thereby promoting endothelial motility in the angiogenic environment. Myct1-deficient endothelial cells facilitated transendothelial migration of cytotoxic T lymphocytes and polarization of M1 macrophages. Myct1 targeting combined with anti-PD1 treatment significantly (P < 0.05) increased complete tumor regression and long-term survival in anti-PD1–responsive and –refractory tumor models in mice. Our data collectively support a critical role for Myct1 in controlling tumor angiogenesis and reprogramming tumor immunity. Myct1-targeted vascular control, in combination with immunotherapy, may become an exciting therapeutic strategy.
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