||Ridge SM, Whiteley AE, Yao H, Price TT, Brockman ML, Murray AS, Simon BG, Islam P, Sipkins DA, Pan-PI3Ki targets multiple B-ALL microenvironment interactions that fuel systemic and CNS relapse., Leukemia and Lymphoma, 62, 11, 2690-2702, 2021.08.
||Gotoh K, Kunisaki Y, Mizuguchi S, Setoyama D, Hosokawa K, Yao H, Nakashima Y, Yagi M, Uchiumi T, Semba Y, Nogami J, Akashi K, Arai F, Kang D., Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45 - TER119 - Erythroid and Lymphoid Progenitors. , iScience, 23, 22, 101654, 2021.11.
||Hisayuki Yao, Trevor T. Price, Gaia Cantelli, Brandon Ngo, Matthew J. Warner, Lindsey Olivere, Sarah M. Ridge, Elizabeth M. Jablonski, Joseph Therrien, Stacey Tannheimer, Chad M. McCall, Anjen Chenn, Dorothy A. Sipkins, Leukaemia hijacks a neural mechanism to invade the central nervous system, Nature, 10.1038/s41586-018-0342-5, 560, 7716, 55-60, 2018.08, Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood–brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin–laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS..
||Yoko Nakagawa, Eishi Ashihara, Hisayuki Yao, Asumi Yokota, Yuki Toda, Yasuo Miura, Susumu Nakata, Hideyo Hirai, Taira Maekawa, Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2018.01.034, 496, 2, 490-496, 2018.02, The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation..