@article{d0dc4bbb17f64ec5a4f9836daa8a8474,
title = "Glioma progression is shaped by genetic evolution and microenvironment interactions",
abstract = "The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.",
keywords = "genomics, glioblastoma, glioma, hypermutation, macrophages, microenvironment, neurons, single-cell, spatial imaging, treatment resistance",
author = "Varn, {Frederick S.} and Johnson, {Kevin C.} and Jan Martinek and Huse, {Jason T.} and Nasrallah, {MacLean P.} and Pieter Wesseling and Cooper, {Lee A.D.} and Malta, {Tathiane M.} and Wade, {Taylor E.} and Sabedot, {Thais S.} and Daniel Brat and Gould, {Peter V.} and Adelheid W{\"o}ehrer and Kenneth Aldape and Azzam Ismail and Sivajothi, {Santhosh K.} and Barthel, {Floris P.} and Hoon Kim and Emre Kocakavuk and Nazia Ahmed and Kieron White and Indrani Datta and Moon, {Hyo Eun} and Steven Pollock and Christine Goldfarb and Lee, {Ga Hyun} and Luciano Garofano and Anderson, {Kevin J.} and Djamel Nehar-Belaid and Barnholtz-Sloan, {Jill S.} and Spyridon Bakas and Byrne, {Annette T.} and Fulvio D'Angelo and Gan, {Hui K.} and Mustafa Khasraw and Simona Migliozzi and Ormond, {D. Ryan} and Paek, {Sun Ha} and {Van Meir}, {Erwin G.} and Walenkamp, {Annemiek M.E.} and Colin Watts and Tobias Weiss and Michael Weller and Karolina Palucka and Stead, {Lucy F.} and Poisson, {Laila M.} and Houtan Noushmehr and Anna Golebiewska and Hau, {Ann C.} and Niclou, {Simone P.} and Verhaak, {Roel G.W.} and {The GLASS Consortium}",
note = "Funding Information: We thank the patients and their families for their generous donations to biomedical research. We gratefully acknowledge the genome technology, single-cell biology, and microscopy services at the Jackson Laboratory for their expert assistance and Z. Reifsnyder (Jackson Laboratory) for the graphic design. We thank R. Puchalski for his helpful suggestions when designing the histopathology validation studies. This work is supported by the National Institutes of Health grants, R01CA237208, R21NS114873, R21CA256575, U2CCA252979 (R.G.W.V.), P30CA034196 (R.G.W.V. and K.P.), R01CA222146 (H.N. L.M.P. and I.D.), P30CA016672, P50CA127001 (J.T.H.), P30CA13148 (E.G.V.M.), U01CA242871, R01NS042645, and U24CA189523 (S.B.); the University of Texas M D Anderson Cancer Center Glioblastoma Moon Shots Program (J.T.H. and D.R.O.); the S{\~a}o Paulo Research Foundation grants 2018/00583-0, 2019/14928-1 (T.M.M.); NCI-FCRDC contract 28XS100 (E.G.V.M.); the Leeds Hospitals Charity grant 9R11/14-11 and UKRI Fellowship MR/T020504/1 (L.F.S.); the Dutch Cancer Society project 11026 (P.W.); European Union's Horizon 2020 GLIOTRAIN initiative (#766069) (A.T.B. and K.W.); the Department of Defense grants CA170278 (H.N. and T.S.S.) and W81XWH1910246 (R.G.W.V.). This work was also supported by generous gifts from the Dabbiere family (R.G.W.V.). Tissue banking within Brain Tumour Northwest is supported by the Sydney Driscoll Neuroscience Foundation and within Leeds by the Yorkshire's Brain Tumour Charity and the OSCAR's Pediatric Brain Tumour Charity. F.P.B. was supported by the JAX Scholar program and the National Cancer Institute (K99CA226387). K.C.J. was the recipient of an American Cancer Society Fellowship (130984-PF-17-141-01-DMC). F.S.V. is supported by the JAX Scholar program and a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. Conceptualization, F.S.V. H.N. A. Iavarone, and R.G.W.V.; methodology, F.S.V.; validation, F.S.V. J.M. J.T.H. M.P.N. P.W. L.A.D.C. D.B. P.V.G. A.W. K.A. A. Ismail, S.K.S. D.N.-B. and K.P.; formal analysis, F.S.V. K.C.J. E.K. N.A. and K.W.; investigation, F.S.V. J.M. S.K.S. G.-L. and C.G.; resources, F.S.V. J.M. J.T.H. P.W. L.A.D.C. T.M.M. A.W. A. Ismail, H.-E.M. S.P. L.G. K.J.A. J.S.B.-S. S.B. H.K.G. D.R.O. S.H.P. E.G.V.M. A.M.E.W. M.W. K.P. L.F.S. L.M.P. and R.G.W.V.; data curation, F.S.V. K.C.J. T.M.M. T.E.W. T.S.S. F.P.B. H.K. N.A. I.D. C.W. D.R.O. L.F.S. and L.M.P.; writing—original draft, F.S.V. R.G.W.V.; writing—review & editing, F.S.V. K.C.J. J.M. J.T.H. P.W. T.M.M. P.V.G. A.W. K.A. F.P.B. E.K. I.D. J.S.B.-S. S.B. H.K.G. M.K. D.R.O. E.G.V.M. A.M.E.W. C.W. T.W. M.W. L.F.S. L.M.P. H.N. A. Iavarone, and R.G.W.V.; supervision, H.N. A. Iavarone, R.G.W.V.; all co-authors and contributors discussed the results and commented on the manuscript. R.G.W.V. is a co-founder of Boundless Bio and a consultant for Stellanova Therapeutics. M.K. has received research funding from AbbVie and Bristol Myers Squibb, and he is on the advisory board for Janssen; he has received honoraria from the Jackson Laboratory. D.R.O. has received funding from Integra and Agios. F.P.B. has performed consulting for Bristol Myers Squibb. M.W. has received research grants from AbbVie, Adastra, Apogenix, Merck, Sharp & Dohme, Novocure, and Quercis and honoraria for lectures or advisory board participation or consulting from AbbVie, Adastra, Basilea, Bristol Meyer Squibb, Celgene, Medac, Merck, Sharp & Dohme, Merck, Nerviano Medical Sciences, Novartis, Orbus, Philogen, Roche, Tocagen, and yMabs. A.M.E.W. reported receiving institutional financial support for an advisory role from Polyphor, IPSEN, Karyopharm, and Novartis; unrestricted research grants from IPSEN and Novartis; and study budgets from AbbVie, BMS, Genzyme, Karyopharm Therapeutics, and Roche, all outside the submitted work. H.K.G. has performed consulting for AbbVie, and he is a member of the speaker bureau for AbbVie and Igynta. K.P. is a scientific advisory board member and owns stock in Cue BioPharma. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = jun,
day = "9",
doi = "10.1016/j.cell.2022.04.038",
language = "English",
volume = "185",
pages = "2184--2199",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "12",
}