Abstract
There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor–resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profi ling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 628-645 |
| Number of pages | 18 |
| Journal | Cancer discovery |
| Volume | 9 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2019 |
ASJC Scopus subject areas
- Oncology
MD Anderson CCSG core facilities
- Biostatistics Resource Group
- Research Animal Support Facility
- Tissue Biospecimen and Pathology Resource
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In: Cancer discovery, Vol. 9, No. 5, 05.2019, p. 628-645.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases
AU - Fischer, Grant M.
AU - Jalali, Ali
AU - Kircher, David A.
AU - Lee, Won Chul
AU - McQuade, Jennifer L.
AU - Haydu, Lauren E.
AU - Joon, Aron Y.
AU - Reuben, Alexandre
AU - de Macedo, Mariana P.
AU - Carapeto, Fernando C.L.
AU - Yang, Chendong
AU - Srivastava, Anuj
AU - Ambati, Chandrashekar R.
AU - Sreekumar, Arun
AU - Hudgens, Courtney W.
AU - Knighton, Barbara
AU - Deng, Wanleng
AU - Ferguson, Sherise D.
AU - Tawbi, Hussein A.
AU - Glitza, Isabella C.
AU - Gershenwald, Jeffrey E.
AU - Vashisht Gopal, Y. N.
AU - Hwu, Patrick
AU - Huse, Jason T.
AU - Wargo, Jennifer A.
AU - Andrew Futreal, P.
AU - Putluri, Nagireddy
AU - Lazar, Alexander J.
AU - Deberardinis, Ralph J.
AU - Marszalek, Joseph R.
AU - Zhang, Jianjun
AU - Holmen, Sheri L.
AU - Tetzlaff, Michael T.
AU - Davies, Michael A.
N1 - Funding Information: G.M. Fischer is supported by The University of Texas MD Anderson Cancer Center (MD Anderson) Caroline Ross Fellowship, the MD Anderson/UT-Health Graduate School of Biomedical Sciences Schissler Foundation Fellowship, and the NIH National Center for Advancing Translational Sciences (TL1TR000369 and UL1TR000371). M.A. Davies is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (R01 CA121118-06A1 and 2T32CA009666-21), the Cancer Prevention Research Institute of Texas (CPRIT; RP170401), and funding from the MD Anderson Multidisciplinary Research Program. M.A. Davies, J.E. Gershenwald., and J.A. Wargo are supported by philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. M.A. Davies and Y.N. Vashisht Gopal are supported by CPRIT (RP160183). Y.N. Vashisht Gopal is supported by the Melanoma Research Alliance Young Investigator Award (348483). J.E. Gershenwald is supported by the Dr. John M. Skibber Professorship of MD Anderson, the Robert and Lynne Grossman Family Foundation, and the Michael and Patricia Booker Melanoma Research Endowment. J.L. McQuade is supported by an ASCO/CCF Young Investigator Award, an MD Anderson Melanoma SPORE Developmental Research Award (P50 CA093459), and an NIH T32 Training Grant Award (CA009666). R.J. DeBerardinis is supported by the NIH/NCI (R35 CA220449) and HHMI (Investigator Program). S.L. Holmen is supported by the NIH/NCI (R01 CA121118) and Melanoma Research Alliance Established Investigator Award (347651). LC/MS experiments were supported by the Metabolomics Core and Population Sciences Biore-pository Core at Baylor College of Medicine with funding from the NIH (P30 CA125123, to A. Sreekumar and N. Putluri) and CPRIT Proteomics and Metabolomics Core Facility (RP170005, to A. Sreekumar and N. Putluri). The LC/MS research was partially supported by the following grants: NIH/NCIR01CA220297 (N. Putluri), NIH/NCIR01CA216426 (N. Putluri), American Cancer Society (ACS) Award 127430-RSG-15-105-01-CNE (N. Putluri), NIH/NCIU01 CA167234 (A. Sreekumar), NIH/NCIUO1 CA179674-01A1, and Agi-lent Technologies Center of Excellence (COE) in Mass Spectrometry Collaboration at Baylor College of Medicine (A. Sreekumar). A. Jalali is supported by the NIH (R25 NS070694). We would like to acknowledge M. Emilia Di Francesco, Timothy McAfoos, and Jason Gay of the Institute for Applied Cancer Science and Center for Co-Clinical Trials at MD Anderson for providing us with the IACS-010759. RNA-seq ICr and SQ xenograft data were processed on the Seven Bridges Cancer Genomics Cloud platform (https://cgc.sbgenomics.com/). Funding Information: G.M. Fischer is supported by The University of Texas MD Anderson Cancer Center (MD Anderson) Caroline Ross Fellowship, the MD Anderson/UT-Health Graduate School of Biomedical Sciences Schissler Foundation Fellowship, and the NIH National Center for Advancing Translational Sciences (TL1TR000369 and UL1TR000371). M.A. Davies is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (R01 CA121118-06A1 and 2T32CA009666-21), the Cancer Prevention Research Institute of Texas (CPRIT; RP170401), and funding from the MD Anderson Multidisciplinary Research Program. M.A. Davies, J.E. Gershenwald., and J.A. Wargo are supported by philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. M.A. Davies and Y.N. Vashisht Gopal are supported by CPRIT (RP160183). Y.N. Vashisht Gopal is supported by the Melanoma Research Alliance Young Investigator Award (348483). J.E. Gershenwald is supported by the Dr. John M. Skibber Professorship of MD Anderson, the Robert and Lynne Grossman Family Foundation, and the Michael and Patricia Booker Melanoma Research Endowment. J.L. McQuade is supported by an ASCO/CCF Young Investigator Award, an MD Anderson Melanoma SPORE Developmental Research Award (P50 CA093459), and an NIH T32 Training Grant Award (CA009666). R.J. DeBerardinis is supported by the NIH/NCI (R35 CA220449) and HHMI (Investigator Program). S.L. Holmen is supported by the NIH/NCI (R01 CA121118) and Melanoma Research Alliance Established Investigator Award (347651). LC/MS experiments were supported by the Metabolomics Core and Population Sciences Biore-pository Core at Baylor College of Medicine with funding from the NIH (P30 CA125123, to A. Sreekumar and N. Putluri) and CPRIT Proteomics and Metabolomics Core Facility (RP170005, to A. Sreekumar and N. Putluri). The LC/MS research was partially supported by the following grants: NIH/NCI R01CA220297 (N. Putluri), NIH/NCI R01CA216426 (N. Putluri), American Cancer Society (ACS) Award 127430-RSG-15-105-01-CNE (N. Putluri), NIH/NCI U01 CA167234 (A. Sreekumar), NIH/NCI UO1 CA179674-01A1, and Agi-lent Technologies Center of Excellence (COE) in Mass Spectrometry Collaboration at Baylor College of Medicine (A. Sreekumar). A. Jalali is supported by the NIH (R25 NS070694). We would like to acknowledge M. Emilia Di Francesco, Timothy McAfoos, and Jason Gay of the Institute for Applied Cancer Science and Center for Co-Clinical Trials at MD Anderson for providing us with the IACS-010759. RNA-seq ICr and SQ xenograft data were processed on the Seven Bridges Cancer Genomics Cloud platform (https://cgc.sbgenomics.com/). Funding Information: H.A. Tawbi reports receiving commercial research support from Bristol-Myers Squibb, Merck, Roche/Genentech, GlaxoSmithKline, and Celgene and is a consultant/advisory board member for Bristol-Myers Squibb, Merck, Roche/Genentech, and Novartis. J.E. Gershen-wald is a consultant/advisory board member for Merck, Bristol-Myers Squibb, Novartis, and Syndax. Y.N. Vashisht Gopal reports receiving a commercial research grant from Calithera Biosciences. P. Hwu is a consultant/advisory board member for Dragonfly, GlaxoSmithKline, Immatics, and Sanofi. J.A. Wargo has received honoraria from the speakers bureaus of Dava Oncology, Illumina, and PHE, and is a consultant/advisory board member for Bristol-Myers Squibb, Novartis, AstraZeneca, Gilead, Roche, and Genentech. R.J. DeBerardinis is a consultant/advisory board member for Agios Pharmaceuticals. M.T. Tetzlaff is a consultant/advisory board member for Novartis LLC, Seattle Genetics, and Myriad Genetics. M.A. Davies reports receiving commercial research grants from AstraZeneca, Roche/Genentech, GlaxoSmithKline, Myriad, Oncothyreon, and Sanofi-Aventis and is a consultant/advisory board member for GlaxoSmithKline, Novartis, Roche/Genentech, Array, Bristol-Myers Squibb, Sanofi-Aventis, Vac-cinex, Syndax, and NanoString. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: © 2019 American Association for Cancer Research.
PY - 2019/5
Y1 - 2019/5
N2 - There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor–resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profi ling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.
AB - There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor–resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profi ling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.
UR - http://www.scopus.com/inward/record.url?scp=85065510180&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065510180&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-18-1489
DO - 10.1158/2159-8290.CD-18-1489
M3 - Article
C2 - 30787016
AN - SCOPUS:85065510180
SN - 2159-8274
VL - 9
SP - 628
EP - 645
JO - Cancer discovery
JF - Cancer discovery
IS - 5
ER -