Multi-scale signaling and tumor evolution in high-grade gliomas
(2024) Cancer Cell, 42 (7), pp. 1217-1238.e19.
Liu, J.a b , Cao, S.a b , Imbach, K.J.c d , Gritsenko, M.A.e , Lih, T.-S.M.f , Kyle, J.E.e , Yaron-Barir, T.M.g h i , Binder, Z.A.j , Li, Y.a b , Strunilin, I.a b , Wang, Y.-T.e , Tsai, C.-F.e , Ma, W.k , Chen, L.f , Clark, N.M.l , Shinkle, A.a b , Naser Al Deen, N.a b , Caravan, W.a b , Houston, A.a b , Simin, F.A.a b , Wyczalkowski, M.A.a b , Wang, L.-B.a b , Storrs, E.a b , Chen, S.a b , Illindala, R.a m n , Li, Y.D.a m n , Jayasinghe, R.G.a b , Rykunov, D.k , Cottingham, S.L.o , Chu, R.K.p , Weitz, K.K.e , Moore, R.J.e , Sagendorf, T.e , Petyuk, V.A.e , Nestor, M.e , Bramer, L.M.e , Stratton, K.G.e , Schepmoes, A.A.e , Couvillion, S.P.e , Eder, J.e , Kim, Y.-M.e , Gao, Y.e , Fillmore, T.L.o , Zhao, R.e , Monroe, M.E.e , Southard-Smith, A.N.a b , Li, Y.E.q r , Jui-Hsien Lu, R.a b , Johnson, J.L.g , Wiznerowicz, M.s t , Hostetter, G.u , Newton, C.J.u , Ketchum, K.A.v , Thangudu, R.R.v , Barnholtz-Sloan, J.S.w , Wang, P.k , Fenyö, D.x y , An, E.z , Thiagarajan, M.aa , Robles, A.I.z , Mani, D.R.l , Smith, R.D.e , Porta-Pardo, E.c , Cantley, L.C.g ab ac , Iavarone, A.ad ae , Chen, F.a m , Mesri, M.z , Nasrallah, M.P.af , Zhang, H.f ag ah , Resnick, A.C.ai aj , Chheda, M.G.a m n , Rodland, K.D.ak , Liu, T.e , Ding, L.a b m q , Philadelphia Coalition for a Cureal , Clinical Proteomic Tumor Analysis Consortiumal
a Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
b McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, United States
c Josep Carreras Leukaemia Research Institute, Badalona, Spain
d Universidad Autónoma de Barcelona, Barcelona, Bellaterra, 08193, Spain
e Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, United States
f Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
g Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, United States
h Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, United States
i Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, United States
j Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
k Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
l The Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
m Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, United States
n Department of Neurology, Washington University in St. Louis, St. Louis, MO 63130, United States
o Department of Pathology, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, MI, United States
p Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, United States
q Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
r Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States
s International Institute for Molecular Oncology, Poznań, Poland
t Poznan University of Medical Sciences, Poznań, Poland
u Van Andel Research Institute, Grand Rapids, MI, United States
v ICF, 530 Gaither Road Suite 500, Rockville, MD 20850, United States
w Center for Biomedical Informatics and Information Technology & Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850, United States
x Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, United States
y Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, United States
z Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, United States
aa Frederick National Laboratory for Cancer Research, Frederick, MD 21701, United States
ab Department of Cell Biology, Harvard Medical School, Boston, MA 02115, United States
ac Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, United States
ad Department of Neurological Surgery and Department of Biochemistry, University of Miami Miller School of Medicine, Miami, FL 33136, United States
ae Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, United States
af Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
ag Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
ah Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
ai Center for Data Driven Discovery in Biomedicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
aj Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
ak Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97221, United States
Abstract
Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas. © 2024 The Authors
Author Keywords
CPTAC; glioblastoma; glycoproteomics; lipidome; metabolome; proteomics; single nuclei ATAC-seq; single nuclei RNA-seq; tumor recurrence
Funding details
Merck
Pacific Northwest National LaboratoryPNNL
U.S. Department of EnergyUSDOE
Orbus Therapeutics
BattelleBMI
DE-AC05-76RL01830
LABAE20038PORT
P41-GM103311
National Institutes of HealthNIHRYC2019-026415-I, PID2019- 107043RA-I00
National Institutes of HealthNIH
National Human Genome Research InstituteNHGRIR01NS107833, R01NS117149
National Human Genome Research InstituteNHGRI
R01HG009711
Document Type: Article
Publication Stage: Final
Source: Scopus
Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (27), pp. e2314702121.
DeSpenza, T., Jra b c , Singh, A.c , Allington, G.d e , Zhao, S.f , Lee, J.g , Kizlitug, E.c , Prina, M.L.g , Desmet, N.g , Dang, H.Q.g , Fields, J.h , Nelson-Williams, C.c , Zhang, J.c , Mekbib, K.Y.c g , Dennis, E.e , Mehta, N.H.e , Duy, P.Q.a , Shimelis, H.i , Walsh, L.K.i , Marlier, A.a , Deniz, E.j , Lake, E.M.R.k , Constable, R.T.k , Hoffman, E.J.a l , Lifton, R.P.m , Gulledge, A.g , Fiering, S.h , Moreno-De-Luca, A.i n , Haider, S.o , Alper, S.L.p q , Jin, S.C.f , Kahle, K.T.c e q r , Luikart, B.W.g
a Interdepartmental Neuroscience Program, Yale School of Medicine, Yale University, CT 06510, New Haven, United States
b Medical Scientist Training Program, Yale School of Medicine, Yale University, CT 06510, New Haven, United States
c Department of Neurosurgery, Yale School of Medicine, Yale University, CT 06510, New Haven, United States
d Department of Pathology, Yale School of Medicine, Yale University, CT 06510, New Haven, United States
e Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, United States
f Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Molecular and Systems Biology, Geisel School of Medicine at DartmouthHanover NH 03755, Jamaica
h Department of Microbiology and Immunology, Geisel School of Medicine at DartmouthHanover NH 03755, Jamaica
i Autism and Developmental Medicine Institute, Geisinger, PA 17821, Danville, United States
j Department of Pediatrics, Yale University School of Medicine, CT 06510, New Haven, United States
k Department of Radiology and Biomedical Imaging, Yale University School of Medicine, CT 06520-8042, New Haven, United States
l Child Study Center, Yale School of Medicine, CT 06510, New Haven, United States
m Laboratory of Human Genetics and Genomics, Rockefeller University, NY, NY 10065, United States
n Department of Radiology, Diagnostic Medicine Institute, Geisinger, PA 17821, Danville, United States
o Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, WC1N 1AX, United Kingdom
p Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, United States
q Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, United Kingdom
r Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
Abstract
Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 (Katnal2Δ17) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.
Author Keywords
autism; cerebrospinal fluid dynamics; ciliopathy; hydrocephalus; structural brain disorder
Document Type: Article
Publication Stage: Final
Source: Scopus
Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography – Computed Tomography Scanner
(2024) Journal of Visualized Experiments: JoVE, (208), .
Lee, J.J.a , Metcalf, N.a , Durbin, T.A.a , Byers, J.a , Casey, K.a , Jafri, H.a , Goyal, M.S.b , Vlassenko, A.G.a
a Mallinckrodt Institute of Radiology, Washington University School of Medicine
b Mallinckrodt Institute of Radiology, Washington University School of Medicine;
Abstract
The authors have developed a paradigm using positron emission tomography (PET) with multiple radiopharmaceutical tracers that combines measurements of cerebral metabolic rate of glucose (CMRGlc), cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV), culminating in estimates of brain aerobic glycolysis (AG). These in vivo estimates of oxidative and non-oxidative glucose metabolism are pertinent to the study of the human brain in health and disease. The latest positron emission tomography-computed tomography (PET-CT) scanners provide time-of-flight (TOF) imaging and critical improvements in spatial resolution and reduction of artifacts. This has led to significantly improved imaging with lower radiotracer doses. Optimized methods for the latest PET-CT scanners involve administering a sequence of inhaled 15O-labeled carbon monoxide (CO) and oxygen (O2), intravenous 15O-labeled water (H2O), and 18F-deoxyglucose (FDG)-all within 2-h or 3-h scan sessions that yield high-resolution, quantitative measurements of CMRGlc, CMRO2, CBF, CBV, and AG. This methods paper describes practical aspects of scanning designed for quantifying brain metabolism with tracer kinetic models and arterial blood samples and provides examples of imaging measurements of human brain metabolism.
Document Type: Article
Publication Stage: Final
Source: Scopus