title: Hedgehog inhibitors selectively target cell migration and adhesion of mantle cell lymphoma in bone marrow microenvironment.
abstract: The clinical benefits of a Hedgehog (Hh) inhibitor, LDE225 (NPV-LDE-225, Erismodegib), have been unclear in hematological cancers. Here, we report that LDE225 selectively inhibited migration and adhesion of mantle cell lymphoma (MCL) to bone marrows via very late antigen-4 (VLA-4) mediated inactivation of focal adhesion kinase (FAK) signaling. LDE225 treatment not only affected MCL cells, but also modulated stromal cells within the bone marrow microenvironment by decreasing their production of SDF-1, IL-6 and VCAM-1, the ligand for VLA-4. Surprisingly, LDE225 treatment alone did not suppress cell proliferation due to increased CXCR4 expression mediated by reactive oxygen species (ROS). The increased ROS/CXCR4 further stimulated autophagy formation. The combination of LDE225 with the autophagy inhibitors further enhanced MCL cell death. Our data, for the first time, revealed LDE225 selectively targets MCL cells migration and adhesion to bone marrows. The ineffectiveness of LDE225 in MCL is due to autophagy formation, which in turn increases cell viability. Inhibiting autophagy will be an effective adjuvant therapy for LDE225 in MCL, especially for advanced MCL patients with bone marrow involvement.
authors.affiliation: Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for The Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for The Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Romaguera
authors.affiliation: Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for The Prevention of Human Diseases (IMM), The University of Texas-Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Nami
authors.initials: N
authors.lastname: McCarty
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; C561435:sonidegib
keywords: adhesion; bone marrow microenvironment; hedgehog; mantle cell lymphoma; migration