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

Molecular Pharmacology

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

45 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 (US)
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 - Jul 7 2022

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

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10.1016/j.cell.2022.06.007

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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

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

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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",

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year = "2022",

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

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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

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SN - 0092-8674

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SP - 2591-2608.e30

JO - Cell

JF - Cell

IS - 14

ER -

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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