@article{RN6051,
   author = {Al-Holou, W. N. and Wang, H. and Ravikumar, V. and Shankar, S. and Oneka, M. and Fehmi, Z. and Verhaak, R. G. and Kim, H. and Pratt, D. and Camelo-Piragua, S. and Speers, C. and Wahl, D. R. and Hollon, T. and Sagher, O. and Heth, J. A. and Muraszko, K. M. and Lawrence, T. S. and de Carvalho, A. C. and Mikkelsen, T. and Rao, A. and Rehemtulla, A.},
   title = {Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma},
   journal = {Neoplasia},
   volume = {36},
   pages = {100872},
   note = {1476-5586
Al-Holou, Wajd N
Wang, Hanxiao
Ravikumar, Visweswaran
Shankar, Sunita
Oneka, Morgan
Fehmi, Ziad
Verhaak, Roel Gw
Kim, Hoon
Pratt, Drew
Camelo-Piragua, Sandra
Speers, Corey
Wahl, Daniel R
Hollon, Todd
Sagher, Oren
Heth, Jason A
Muraszko, Karin M
Lawrence, Theodore S
de Carvalho, Ana C
Mikkelsen, Tom
Rao, Arvind
Rehemtulla, Alnawaz
K08 CA234416/CA/NCI NIH HHS/United States
Journal Article
United States
2023/01/10
Neoplasia. 2023 Feb;36:100872. doi: 10.1016/j.neo.2022.100872. Epub 2023 Jan 6.},
   abstract = {PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.},
   keywords = {Animals
Mice
Humans
*Glioblastoma/metabolism
Cell Line, Tumor
*Brain Neoplasms/pathology
Neoplasm Recurrence, Local/genetics/drug therapy
Temozolomide/pharmacology
Drug Resistance, Neoplasm/genetics
Antineoplastic Agents, Alkylating/pharmacology
Glioblastoma
Subclonal evolution
Treatment resistance},
   ISSN = {1522-8002 (Print)
1476-5586},
   DOI = {10.1016/j.neo.2022.100872},
   year = {2023},
   type = {Journal Article}
}

{"_id":"59mxqsoJRvWva7Kg4","bibbaseid":"alholou-wang-ravikumar-shankar-oneka-fehmi-verhaak-kim-etal-subclonalevolutionandexpansionofspatiallydistinctthy1positivecellsisassociatedwithrecurrenceinglioblastoma-2023","author_short":["Al-Holou, W. N.","Wang, H.","Ravikumar, V.","Shankar, S.","Oneka, M.","Fehmi, Z.","Verhaak, R. G.","Kim, H.","Pratt, D.","Camelo-Piragua, S.","Speers, C.","Wahl, D. R.","Hollon, T.","Sagher, O.","Heth, J. A.","Muraszko, K. M.","Lawrence, T. S.","de Carvalho, A. C.","Mikkelsen, T.","Rao, A.","Rehemtulla, A."],"bibdata":{"bibtype":"article","type":"Journal Article","author":[{"propositions":[],"lastnames":["Al-Holou"],"firstnames":["W.","N."],"suffixes":[]},{"propositions":[],"lastnames":["Wang"],"firstnames":["H."],"suffixes":[]},{"propositions":[],"lastnames":["Ravikumar"],"firstnames":["V."],"suffixes":[]},{"propositions":[],"lastnames":["Shankar"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Oneka"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Fehmi"],"firstnames":["Z."],"suffixes":[]},{"propositions":[],"lastnames":["Verhaak"],"firstnames":["R.","G."],"suffixes":[]},{"propositions":[],"lastnames":["Kim"],"firstnames":["H."],"suffixes":[]},{"propositions":[],"lastnames":["Pratt"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Camelo-Piragua"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Speers"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Wahl"],"firstnames":["D.","R."],"suffixes":[]},{"propositions":[],"lastnames":["Hollon"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Sagher"],"firstnames":["O."],"suffixes":[]},{"propositions":[],"lastnames":["Heth"],"firstnames":["J.","A."],"suffixes":[]},{"propositions":[],"lastnames":["Muraszko"],"firstnames":["K.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Lawrence"],"firstnames":["T.","S."],"suffixes":[]},{"propositions":["de"],"lastnames":["Carvalho"],"firstnames":["A.","C."],"suffixes":[]},{"propositions":[],"lastnames":["Mikkelsen"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Rao"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Rehemtulla"],"firstnames":["A."],"suffixes":[]}],"title":"Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma","journal":"Neoplasia","volume":"36","pages":"100872","note":"1476-5586 Al-Holou, Wajd N Wang, Hanxiao Ravikumar, Visweswaran Shankar, Sunita Oneka, Morgan Fehmi, Ziad Verhaak, Roel Gw Kim, Hoon Pratt, Drew Camelo-Piragua, Sandra Speers, Corey Wahl, Daniel R Hollon, Todd Sagher, Oren Heth, Jason A Muraszko, Karin M Lawrence, Theodore S de Carvalho, Ana C Mikkelsen, Tom Rao, Arvind Rehemtulla, Alnawaz K08 CA234416/CA/NCI NIH HHS/United States Journal Article United States 2023/01/10 Neoplasia. 2023 Feb;36:100872. doi: 10.1016/j.neo.2022.100872. Epub 2023 Jan 6.","abstract":"PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.","keywords":"Animals Mice Humans *Glioblastoma/metabolism Cell Line, Tumor *Brain Neoplasms/pathology Neoplasm Recurrence, Local/genetics/drug therapy Temozolomide/pharmacology Drug Resistance, Neoplasm/genetics Antineoplastic Agents, Alkylating/pharmacology Glioblastoma Subclonal evolution Treatment resistance","issn":"1522-8002 (Print) 1476-5586","doi":"10.1016/j.neo.2022.100872","year":"2023","bibtex":"@article{RN6051,\n author = {Al-Holou, W. N. and Wang, H. and Ravikumar, V. and Shankar, S. and Oneka, M. and Fehmi, Z. and Verhaak, R. G. and Kim, H. and Pratt, D. and Camelo-Piragua, S. and Speers, C. and Wahl, D. R. and Hollon, T. and Sagher, O. and Heth, J. A. and Muraszko, K. M. and Lawrence, T. S. and de Carvalho, A. C. and Mikkelsen, T. and Rao, A. and Rehemtulla, A.},\n title = {Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma},\n journal = {Neoplasia},\n volume = {36},\n pages = {100872},\n note = {1476-5586\nAl-Holou, Wajd N\nWang, Hanxiao\nRavikumar, Visweswaran\nShankar, Sunita\nOneka, Morgan\nFehmi, Ziad\nVerhaak, Roel Gw\nKim, Hoon\nPratt, Drew\nCamelo-Piragua, Sandra\nSpeers, Corey\nWahl, Daniel R\nHollon, Todd\nSagher, Oren\nHeth, Jason A\nMuraszko, Karin M\nLawrence, Theodore S\nde Carvalho, Ana C\nMikkelsen, Tom\nRao, Arvind\nRehemtulla, Alnawaz\nK08 CA234416/CA/NCI NIH HHS/United States\nJournal Article\nUnited States\n2023/01/10\nNeoplasia. 2023 Feb;36:100872. doi: 10.1016/j.neo.2022.100872. Epub 2023 Jan 6.},\n abstract = {PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.},\n keywords = {Animals\nMice\nHumans\n*Glioblastoma/metabolism\nCell Line, Tumor\n*Brain Neoplasms/pathology\nNeoplasm Recurrence, Local/genetics/drug therapy\nTemozolomide/pharmacology\nDrug Resistance, Neoplasm/genetics\nAntineoplastic Agents, Alkylating/pharmacology\nGlioblastoma\nSubclonal evolution\nTreatment resistance},\n ISSN = {1522-8002 (Print)\n1476-5586},\n DOI = {10.1016/j.neo.2022.100872},\n year = {2023},\n type = {Journal Article}\n}\n\n","author_short":["Al-Holou, W. N.","Wang, H.","Ravikumar, V.","Shankar, S.","Oneka, M.","Fehmi, Z.","Verhaak, R. G.","Kim, H.","Pratt, D.","Camelo-Piragua, S.","Speers, C.","Wahl, D. R.","Hollon, T.","Sagher, O.","Heth, J. A.","Muraszko, K. M.","Lawrence, T. S.","de Carvalho, A. C.","Mikkelsen, T.","Rao, A.","Rehemtulla, A."],"key":"RN6051","id":"RN6051","bibbaseid":"alholou-wang-ravikumar-shankar-oneka-fehmi-verhaak-kim-etal-subclonalevolutionandexpansionofspatiallydistinctthy1positivecellsisassociatedwithrecurrenceinglioblastoma-2023","role":"author","urls":{},"keyword":["Animals Mice Humans *Glioblastoma/metabolism Cell Line","Tumor *Brain Neoplasms/pathology Neoplasm Recurrence","Local/genetics/drug therapy Temozolomide/pharmacology Drug Resistance","Neoplasm/genetics Antineoplastic Agents","Alkylating/pharmacology Glioblastoma Subclonal evolution Treatment resistance"],"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://verhaaklab.com/files/verhaak.bib","dataSources":["iFXeF2qjAL2y5TeTz"],"keywords":["animals mice humans *glioblastoma/metabolism cell line","tumor *brain neoplasms/pathology neoplasm recurrence","local/genetics/drug therapy temozolomide/pharmacology drug resistance","neoplasm/genetics antineoplastic agents","alkylating/pharmacology glioblastoma subclonal evolution treatment resistance"],"search_terms":["subclonal","evolution","expansion","spatially","distinct","thy1","positive","cells","associated","recurrence","glioblastoma","al-holou","wang","ravikumar","shankar","oneka","fehmi","verhaak","kim","pratt","camelo-piragua","speers","wahl","hollon","sagher","heth","muraszko","lawrence","de carvalho","mikkelsen","rao","rehemtulla"],"title":"Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma","year":2023}