Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 55-60 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 560 |
| Issue number | 7716 |
| DOIs | |
| Publication status | Published - Aug 2 2018 |
| Externally published | Yes |
Fingerprint
All Science Journal Classification (ASJC) codes
- General
Cite this
Leukaemia hijacks a neural mechanism to invade the central nervous system. / Yao, Hisayuki; Price, Trevor T.; Cantelli, Gaia; Ngo, Brandon; Warner, Matthew J.; Olivere, Lindsey; Ridge, Sarah M.; Jablonski, Elizabeth M.; Therrien, Joseph; Tannheimer, Stacey; McCall, Chad M.; Chenn, Anjen; Sipkins, Dorothy A.
In: Nature, Vol. 560, No. 7716, 02.08.2018, p. 55-60.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Leukaemia hijacks a neural mechanism to invade the central nervous system
AU - Yao, Hisayuki
AU - Price, Trevor T.
AU - Cantelli, Gaia
AU - Ngo, Brandon
AU - Warner, Matthew J.
AU - Olivere, Lindsey
AU - Ridge, Sarah M.
AU - Jablonski, Elizabeth M.
AU - Therrien, Joseph
AU - Tannheimer, Stacey
AU - McCall, Chad M.
AU - Chenn, Anjen
AU - Sipkins, Dorothy A.
PY - 2018/8/2
Y1 - 2018/8/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85050987296&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050987296&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0342-5
DO - 10.1038/s41586-018-0342-5
M3 - Article
C2 - 30022166
AN - SCOPUS:85050987296
VL - 560
SP - 55
EP - 60
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7716
ER -