Trending With Impact: Hedgehog Signaling Induces Proliferation in Gastric Cancer

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Oncotarget

Oncotarget published this trending research paper on December 21, 2018, entitled, "Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer" by researchers from the Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH; Department of Dermatology, University of Michigan, Ann Arbor, MI; Division of Developmental Biology, University of Michigan, Ann Arbor, MI; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH; Department of Surgery, University of Cincinnati Cancer Institute, Cincinnati, OH; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI. Abstract: Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation. Mouse organoids were generated from tumors of a triple-transgenic mouse model engineered to express an activated GLI2 allele, GLI2A, in Lgr5-expressing stem cells, (mTGOs) or normal mouse stomachs (mGOs). Bone marrow-derived dendritic cells (DCs) were pulsed with conditioned media collected from normal (mGOCM) or cancer (mTGOCM) organoids. Pulsed DCs and CTLs were then co-cultured with either mGOs or mTGOs in the presence of PD-L1 neutralizing antibody (PD-L1Ab). Human-derived gastric cancer organoids (huTGOs) were used in drug and xenograft assays. Hh/Gli inhibitor, GANT-61 significantly reduced the expression of PD-L1 and tumor cell proliferation both in vivo and in vitro. PD-L1Ab treatment induced tumor cell apoptosis in mTGO/immune cell co-cultures. GANT-61 treatment sensitized huTGOs to standard-of-care chemotherapeutic drugs both in vivo and in vitro. Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.26473 DOI - https://doi.org/10.18632/oncotarget.26473 Full text - https://www.oncotarget.com/article/26473/text/ Correspondence to - Yana Zavros - yana.zavros@uc.edu Keywords - gastric cancer organoids, PD-1, cytotoxic T lymphocytes, dendritic cells About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957