Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Jana Biermann; Johannes C. Melms; Amit Dipak Amin; Yiping Wang; Lindsay A. Caprio; Alcida Karz; Somnath Tagore; Irving Barrera; Miguel A. Ibarra-Arellano; Massimo Andreatta; Benjamin T. Fullerton; Kristjan H. Gretarsson; Varun Sahu; Vaibhav S. Mangipudy; Trang T.T. Nguyen; Ajay Nair; Meri Rogava; Patricia Ho; Peter D. Koch; Matei Banu; Nelson Humala; Aayushi Mahajan; Zachary H. Walsh; Shivem B. Shah; Daniel H. Vaccaro; Blake Caldwell; Michael Mu; Florian Wünnemann; Margot Chazotte; Simon Berhe; Adrienne M. Luoma; Joseph Driver; Matthew Ingham; Shaheer A. Khan; Suthee Rapisuwon; Craig L. Slingluff; Thomas Eigentler; Martin Röcken; Richard Carvajal; Michael B. Atkins; Michael A. Davies; Albert Agustinus; Samuel F. Bakhoum; Elham Azizi; Markus Siegelin; Chao Lu; Santiago J. Carmona; Hanina Hibshoosh; Antoni Ribas; Peter Canoll; Jeffrey N. Bruce; Wenya Linda Bi; Praveen Agrawal; Denis Schapiro; Eva Hernando; Evan Z. Macosko; Fei Chen; Gary K. Schwartz; Benjamin Izar

doi:10.1016/j.cell.2022.06.007

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Jana Biermann, Johannes C. Melms, Amit Dipak Amin, Yiping Wang, Lindsay A. Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A. Ibarra-Arellano, Massimo Andreatta, Benjamin T. Fullerton, Kristjan H. Gretarsson, Varun Sahu, Vaibhav S. Mangipudy, Trang T.T. Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D. Koch, Matei BanuNelson Humala, Aayushi Mahajan, Zachary H. Walsh, Shivem B. Shah, Daniel H. Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M. Luoma, Joseph Driver, Matthew Ingham, Shaheer A. Khan, Suthee Rapisuwon, Craig L. Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B. Atkins, Michael A. Davies, Albert Agustinus, Samuel F. Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J. Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N. Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z. Macosko, Fei Chen, Gary K. Schwartz, Benjamin Izar

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

Abstract

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX⁺CD8⁺ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Original language	English
Pages (from-to)	2591-2608.e30
Journal	Cell
Volume	185
Issue number	14
DOIs	https://doi.org/10.1016/j.cell.2022.06.007
State	Published - 7 Jul 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Funding

We thank Robert Schwabe (Columbia University) for fruitful discussions, Iman Osman (Melanoma Program, NYU Langone Health) for providing the 12-273BM and 12-273LN melanoma short-term cultures, and Robert S. Kerbel (University of Toronto) for providing the 4L and 5B1 melanoma cell lines. B.I. is supported by National Institute of Health (NIH) National Cancer Institute (NCI) grants K08CA222663 , R37CA258829 , U54CA225088 , and R21CA263381 (with E.A. and R.C.); an American Cancer Society Research Scholar Grant; a Burroughs Wellcome Fund Career Award for Medical Scientists; a Velocity Fellows Award; the Louis V. Gerstner, Jr. Scholars Program; a V Foundation Scholar Award; a Columbia University RISE award (with E.A. and R.C.); and the Tara Miller Young Investigator Award by the Melanoma Research Alliance . L.A.C., P.H., Z.H.W., and M.M. are supported by a NIH grant T32GM007367 . M.A.D. is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation , the AIM at Melanoma Foundation , the NIH/NCI ( P50CA221703 ), the American Cancer Society and the Melanoma Research Alliance , Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. A.A. is supported by a PhRMA Foundation Predoctoral Fellowship. M. Röcken and T.E. are supported by Wilhelm Sander-Stiftung ( 2020.100.1 ), DFG RO 764/15-2, Cluster of Excellence iFIT ( EXC 2180 ) “Image-Guided and Functionally Instructed Tumor Therapies,” University of Tübingen, Germany, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanyʼs Excellence Strategy ( EXC 2180 – 390900677 ) and acknowledge project support from S. Forchhammer and F. Fend. M.B.A. is supported by the NIH/NCI ( P30CA051008 ), a Melanoma Research Alliance Senior Scientist Award, and the William M. Scholl Chair for Cancer Research. D.S. is supported by the German Federal Ministry of Education and Research ( BMBF 01ZZ2004 ). E.H. contributions were supported by a Melanoma Research Alliance (MRA)/ American Cancer Society (ACS) Team award and the NYU Melanoma SPORE P50 CA225450 . A.K. is supported by the NYU Medical Scientist Training program (MSTP; 5T32GM136573 ). We thank the NYULH Genomics Technology Center, Preclinical Imaging and Experimental Pathology Cores, which are partially supported by the Cancer Center Support Grant NIH/NCI P30 CA016087 to the Perlmutter Cancer Center at NYULH. Illustrations were created with BioRender.com. This work was supported by NIH/NCI Cancer Center Support grant P30CA013696 , including the Oncology Precision Therapeutics and Imaging Core and the Molecular Pathology Shared Resource, and its Tissue Bank at Columbia University. We thank Robert Schwabe (Columbia University) for fruitful discussions, Iman Osman (Melanoma Program, NYU Langone Health) for providing the 12-273BM and 12-273LN melanoma short-term cultures, and Robert S. Kerbel (University of Toronto) for providing the 4L and 5B1 melanoma cell lines. B.I. is supported by National Institute of Health (NIH) National Cancer Institute (NCI) grants K08CA222663, R37CA258829, U54CA225088, and R21CA263381 (with E.A. and R.C.); an American Cancer Society Research Scholar Grant; a Burroughs Wellcome Fund Career Award for Medical Scientists; a Velocity Fellows Award; the Louis V. Gerstner, Jr. Scholars Program; a V Foundation Scholar Award; a Columbia University RISE award (with E.A. and R.C.); and the Tara Miller Young Investigator Award by the Melanoma Research Alliance. L.A.C. P.H. Z.H.W. and M.M. are supported by a NIH grant T32GM007367. M.A.D. is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (P50CA221703), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. A.A. is supported by a PhRMA Foundation Predoctoral Fellowship. M. Röcken and T.E. are supported by Wilhelm Sander-Stiftung (2020.100.1), DFG RO 764/15-2, Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies,” University of Tübingen, Germany, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanyʼs Excellence Strategy (EXC 2180 – 390900677) and acknowledge project support from S. Forchhammer and F. Fend. M.B.A. is supported by the NIH/NCI (P30CA051008), a Melanoma Research Alliance Senior Scientist Award, and the William M. Scholl Chair for Cancer Research. D.S. is supported by the German Federal Ministry of Education and Research (BMBF 01ZZ2004). E.H. contributions were supported by a Melanoma Research Alliance (MRA)/American Cancer Society (ACS) Team award and the NYU Melanoma SPORE P50 CA225450. A.K. is supported by the NYU Medical Scientist Training program (MSTP; 5T32GM136573). We thank the NYULH Genomics Technology Center, Preclinical Imaging and Experimental Pathology Cores, which are partially supported by the Cancer Center Support Grant NIH/NCI P30 CA016087 to the Perlmutter Cancer Center at NYULH. Illustrations were created with BioRender.com. This work was supported by NIH/NCI Cancer Center Support grant P30CA013696, including the Oncology Precision Therapeutics and Imaging Core and the Molecular Pathology Shared Resource, and its Tissue Bank at Columbia University. B.I. provided overall supervision of the study. J.C.M. W.L.B. and B.I. conceptualized the study. J.C.M. A.D.A. L.A.C. A.K. I.B. B.T.F. T.T.T.N. M. Rogava, P.H. M.B. N.H. A.M. Z.H.W. S.B.S. D.H.V. M.M. S.B. A.M.L. A.A. and P.A. performed experiments. M.I. S.A.K. J.D. C.L.S. T.E. M. Röcken, R.C. M.B.A. M.A.D. W.L.B. A.R. P.C. J.N.B. G.K.S. and B.I. took care of patients and provided critical tissue resources. J.B. J.C.M. A.D.A. Y.W. A.K. S.T. M.A.I.-A. M.A. K.H.G. V.S.M. V.S. A.N. P.D.K. F.W. M.C. B.C. E.A. S.J.C. and B.I. performed analyses. S.F.B. M.S. C.L. S.J.C. P.C. J.N.B. W.L.B. D.S. E.H. E.Z.M. and F.C. provided additional supervision. H.H. and P.C. performed pathological review of tissue specimens. J.C.M. J.B. A.D.A. Y.W. S.T. and B.I. wrote the manuscript. B.I. has received honoraria from consulting with Merck, Janssen Pharmaceuticals, Astra Zeneca, and Volastra Therapeutics. M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer (New York, NY, United States of America), Novartis, BMS, GSK, Sanofi-Aventis (Bridgewater, NJ, United States of America), Vaccinex, Apexigen, EISAI, and ABM Therapeutics and he has been the PI of research grants to MD Anderson by Roche/Genentech (South San Francisco, CA, United States of America), GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. A.R. has received honoraria from consulting with CStone, Merck, and Vedanta, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine, and Tango, has received research funding from Agilent (Santa Clara, CA, United States of America) and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. T.E. has acted as a consultant for Almiral Hermal, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. E.Z.M. is a consultant for Curio Bioscience. The other authors do not declare competing interests.

Funders	Funder number
Curio Bioscience
CytomX
ImaginAb
MSTP	P30 CA016087, 5T32GM136573
NYU Medical Scientist Training program
Volastra Therapeutics
National Institutes of Health
American Cancer Society
National Cancer Institute	U54CA225088, R21CA263381, P30CA013696, P30CA051008, P50CA221703, K08CA222663, R37CA258829
National Institute of General Medical Sciences	T32GM136573
Burroughs Wellcome Fund
V Foundation for Cancer Research
Pharmaceutical Research and Manufacturers of America Foundation
Melanoma Research Foundation
Bristol-Myers Squibb
AstraZeneca
GlaxoSmithKline
Merck
Novartis
Sanofi
Melanoma Research Alliance	T32GM007367
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Columbia University
Wilhelm Sander-Stiftung	EXC 2180, RO 764/15-2, 2020.100.1
Janssen Pharmaceuticals
Stand Up To Cancer
Myriad Genetics
Deutsche Forschungsgemeinschaft	EXC 2180 – 390900677
Eberhard Karls Universität Tübingen
Bundesministerium für Bildung und Forschung	P50 CA225450, 01ZZ2004

Keywords

brain metastasis
chromosomal instability
melanoma
neuronal-like cell state
single-cell genomics
spatial transcriptomics
tumor-microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2022.06.007

Cite this

Biermann, J., Melms, J. C., Amin, A. D., Wang, Y., Caprio, L. A., Karz, A., Tagore, S., Barrera, I., Ibarra-Arellano, M. A., Andreatta, M., Fullerton, B. T., Gretarsson, K. H., Sahu, V., Mangipudy, V. S., Nguyen, T. T. T., Nair, A., Rogava, M., Ho, P., Koch, P. D., ... Izar, B. (2022). Dissecting the treatment-naive ecosystem of human melanoma brain metastasis. Cell, 185(14), 2591-2608.e30. https://doi.org/10.1016/j.cell.2022.06.007

@article{7293ca05d32f4ce3b96575650da6f667,

title = "Dissecting the treatment-naive ecosystem of human melanoma brain metastasis",

abstract = "Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.",

keywords = "brain metastasis, chromosomal instability, melanoma, neuronal-like cell state, single-cell genomics, spatial transcriptomics, tumor-microenvironment",

author = "Jana Biermann and Melms, {Johannes C.} and Amin, {Amit Dipak} and Yiping Wang and Caprio, {Lindsay A.} and Alcida Karz and Somnath Tagore and Irving Barrera and Ibarra-Arellano, {Miguel A.} and Massimo Andreatta and Fullerton, {Benjamin T.} and Gretarsson, {Kristjan H.} and Varun Sahu and Mangipudy, {Vaibhav S.} and Nguyen, {Trang T.T.} and Ajay Nair and Meri Rogava and Patricia Ho and Koch, {Peter D.} and Matei Banu and Nelson Humala and Aayushi Mahajan and Walsh, {Zachary H.} and Shah, {Shivem B.} and Vaccaro, {Daniel H.} and Blake Caldwell and Michael Mu and Florian W{\"u}nnemann and Margot Chazotte and Simon Berhe and Luoma, {Adrienne M.} and Joseph Driver and Matthew Ingham and Khan, {Shaheer A.} and Suthee Rapisuwon and Slingluff, {Craig L.} and Thomas Eigentler and Martin R{\"o}cken and Richard Carvajal and Atkins, {Michael B.} and Davies, {Michael A.} and Albert Agustinus and Bakhoum, {Samuel F.} and Elham Azizi and Markus Siegelin and Chao Lu and Carmona, {Santiago J.} and Hanina Hibshoosh and Antoni Ribas and Peter Canoll and Bruce, {Jeffrey N.} and Bi, {Wenya Linda} and Praveen Agrawal and Denis Schapiro and Eva Hernando and Macosko, {Evan Z.} and Fei Chen and Schwartz, {Gary K.} and Benjamin Izar",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = jul,

day = "7",

doi = "10.1016/j.cell.2022.06.007",

language = "אנגלית",

volume = "185",

pages = "2591--2608.e30",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "14",

}

Biermann, J, Melms, JC, Amin, AD, Wang, Y, Caprio, LA, Karz, A, Tagore, S, Barrera, I, Ibarra-Arellano, MA, Andreatta, M, Fullerton, BT, Gretarsson, KH, Sahu, V, Mangipudy, VS, Nguyen, TTT, Nair, A, Rogava, M, Ho, P, Koch, PD, Banu, M, Humala, N, Mahajan, A, Walsh, ZH, Shah, SB, Vaccaro, DH, Caldwell, B, Mu, M, Wünnemann, F, Chazotte, M, Berhe, S, Luoma, AM, Driver, J, Ingham, M, Khan, SA, Rapisuwon, S, Slingluff, CL, Eigentler, T, Röcken, M, Carvajal, R, Atkins, MB, Davies, MA, Agustinus, A, Bakhoum, SF, Azizi, E, Siegelin, M, Lu, C, Carmona, SJ, Hibshoosh, H, Ribas, A, Canoll, P, Bruce, JN, Bi, WL, Agrawal, P, Schapiro, D, Hernando, E, Macosko, EZ, Chen, F, Schwartz, GK & Izar, B 2022, 'Dissecting the treatment-naive ecosystem of human melanoma brain metastasis', Cell, vol. 185, no. 14, pp. 2591-2608.e30. https://doi.org/10.1016/j.cell.2022.06.007

TY - JOUR

T1 - Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

AU - Biermann, Jana

AU - Melms, Johannes C.

AU - Amin, Amit Dipak

AU - Wang, Yiping

AU - Caprio, Lindsay A.

AU - Karz, Alcida

AU - Tagore, Somnath

AU - Barrera, Irving

AU - Ibarra-Arellano, Miguel A.

AU - Andreatta, Massimo

AU - Fullerton, Benjamin T.

AU - Gretarsson, Kristjan H.

AU - Sahu, Varun

AU - Mangipudy, Vaibhav S.

AU - Nguyen, Trang T.T.

AU - Nair, Ajay

AU - Rogava, Meri

AU - Ho, Patricia

AU - Koch, Peter D.

AU - Banu, Matei

AU - Humala, Nelson

AU - Mahajan, Aayushi

AU - Walsh, Zachary H.

AU - Shah, Shivem B.

AU - Vaccaro, Daniel H.

AU - Caldwell, Blake

AU - Mu, Michael

AU - Wünnemann, Florian

AU - Chazotte, Margot

AU - Berhe, Simon

AU - Luoma, Adrienne M.

AU - Driver, Joseph

AU - Ingham, Matthew

AU - Khan, Shaheer A.

AU - Rapisuwon, Suthee

AU - Slingluff, Craig L.

AU - Eigentler, Thomas

AU - Röcken, Martin

AU - Carvajal, Richard

AU - Atkins, Michael B.

AU - Davies, Michael A.

AU - Agustinus, Albert

AU - Bakhoum, Samuel F.

AU - Azizi, Elham

AU - Siegelin, Markus

AU - Lu, Chao

AU - Carmona, Santiago J.

AU - Hibshoosh, Hanina

AU - Ribas, Antoni

AU - Canoll, Peter

AU - Bruce, Jeffrey N.

AU - Bi, Wenya Linda

AU - Agrawal, Praveen

AU - Schapiro, Denis

AU - Hernando, Eva

AU - Macosko, Evan Z.

AU - Chen, Fei

AU - Schwartz, Gary K.

AU - Izar, Benjamin

PY - 2022/7/7

Y1 - 2022/7/7

N2 - Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

AB - Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

KW - brain metastasis

KW - chromosomal instability

KW - melanoma

KW - neuronal-like cell state

KW - single-cell genomics

KW - spatial transcriptomics

KW - tumor-microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85133186847&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.06.007

DO - 10.1016/j.cell.2022.06.007

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35803246

AN - SCOPUS:85133186847

SN - 0092-8674

VL - 185

SP - 2591-2608.e30

JO - Cell

JF - Cell

IS - 14

ER -

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this