Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma

Clémentine Sarkozy¹, Shaocheng Wu², Katsuyoshi Takata³, Tomohiro Aoki⁴, Susana B Neriah³, Katy Milne⁵, Talia Goodyear⁵, Celia Strong⁵, Tashi Rastogi⁵, Laura K Hilton³, Daniel Lai², Laurie H Sehn³, Pedro Farinha³, Brad H Nelson⁶, Andrew Weng⁷, Marco Marra⁸, David W Scott³, Jeffrey W Craig⁹, Christian Steidl¹⁰, Andrew Roth¹¹

Affiliations

¹ Hematology Department, Institut Curie, Saint Cloud, France; University PSL, Inserm U1288, Laboratoire d'Imagerie Translationnelle en Oncologie, 91400 Orsay, France.
² Department of Molecular Oncology, British Columbia Cancer, Vancouver, BC, Canada.
³ Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada.
⁴ Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁵ Deeley Research Centre, British Columbia Cancer, Vancouver, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
⁶ Deeley Research Centre, British Columbia Cancer, Vancouver, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁷ Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada.
⁸ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer, Vancouver, BC, Canada.
⁹ Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA.
¹⁰ Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Molecular Oncology, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Computer Science, University of British Columbia, Vancouver, BC, Canada. Electronic address: aroth@bccrc.ca.

PMID: 38861923
DOI: 10.1016/j.ccell.2024.05.011

Free article

Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma

Clémentine Sarkozy et al. Cancer Cell. 2024.

Free article

. 2024 Jun 10;42(6):1003-1017.e6.

doi: 10.1016/j.ccell.2024.05.011.

Authors

Affiliations

¹ Hematology Department, Institut Curie, Saint Cloud, France; University PSL, Inserm U1288, Laboratoire d'Imagerie Translationnelle en Oncologie, 91400 Orsay, France.
² Department of Molecular Oncology, British Columbia Cancer, Vancouver, BC, Canada.
³ Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada.
⁴ Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁵ Deeley Research Centre, British Columbia Cancer, Vancouver, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
⁶ Deeley Research Centre, British Columbia Cancer, Vancouver, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁷ Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada.
⁸ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer, Vancouver, BC, Canada.
⁹ Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA.
¹⁰ Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Molecular Oncology, British Columbia Cancer, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Computer Science, University of British Columbia, Vancouver, BC, Canada. Electronic address: aroth@bccrc.ca.

PMID: 38861923
DOI: 10.1016/j.ccell.2024.05.011

Erratum in

Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma.
Sarkozy C, Wu S, Takata K, Aoki T, Neriah SB, Milne K, Goodyear T, Strong C, Rastogi T, Hilton LK, Lai D, Sehn LH, Farinha P, Nelson BH, Weng A, Marra M, Scott DW, Craig JW, Steidl C, Roth A. Sarkozy C, et al. Cancer Cell. 2024 Sep 9;42(9):1630. doi: 10.1016/j.ccell.2024.07.012. Epub 2024 Aug 15. Cancer Cell. 2024. PMID: 39151424 No abstract available.

Abstract

Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.

Keywords: Follicular lymphoma; single cell; transformation.

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Conflict of interest statement

Declaration of interests C.S. has performed consultancy for AbbVie and Bayer and has received research funding from Epizyme and Trillium Therapeutics. C.Sa has performed consultancy for Incyte Bioscience, BMS-Celgene and Gilead, received research fundings from Roche and BMS, and received travel/congress fundings from Roche, Incyte Bioscience, and AstraZeneca.

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Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma

Affiliations

Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

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