Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level

Lukas John, Alexandra M. Poos, Alexander Brobeil, Carolina Schinke, Stefanie Huhn, Nina Prokoph, Raphael Lutz, Barbara Wagner, Maurizio Zangari, Stephan M. Tirier, Jan-Philipp Mallm, Sabrina Schumacher, Dominik Vonficht, Llorenç Solé-Boldo, Sabine Quick, Simon Steiger, Moritz J. Przybilla, Katharina Bauer, Anja Baumann, Stefan Hemmer, Christoph Rehnitz, Christian Lückerath, Christos Sachpekidis, Gunhild Mechtersheimer, Uwe Haberkorn, Antonia Dimitrakopoulou-Strauss, Philipp Reichert, Bart Barlogie, Carsten Müller-Tidow, Hartmut Goldschmidt, Jens Hillengass, Leo Rasche, Simon F. Haas, Frits Rhee, Karsten Rippe, Marc S. Raab, Sandra Sauer and Niels Weinhold ()
Additional contact information
Lukas John: Heidelberg University Hospital
Alexandra M. Poos: Heidelberg University Hospital
Alexander Brobeil: Heidelberg University Hospital
Carolina Schinke: University of Arkansas for Medical Sciences
Stefanie Huhn: Heidelberg University Hospital
Nina Prokoph: Heidelberg University Hospital
Raphael Lutz: Heidelberg University Hospital
Barbara Wagner: Heidelberg University Hospital
Maurizio Zangari: University of Arkansas for Medical Sciences
Stephan M. Tirier: German Cancer Research Center (DKFZ) and BioQuant
Jan-Philipp Mallm: German Cancer Research Center (DKFZ) and BioQuant
Sabrina Schumacher: German Cancer Research Center (DKFZ) and BioQuant
Dominik Vonficht: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Llorenç Solé-Boldo: Institute of Health (BIH) at Charité—Universitätsmedizin Berlin
Sabine Quick: Heidelberg University Hospital
Simon Steiger: German Cancer Research Center (DKFZ) and BioQuant
Moritz J. Przybilla: German Cancer Research Center (DKFZ)
Katharina Bauer: German Cancer Research Center (DKFZ) and BioQuant
Anja Baumann: Heidelberg University Hospital
Stefan Hemmer: Heidelberg University Hospital
Christoph Rehnitz: Heidelberg University Hospital
Christian Lückerath: Heidelberg University Hospital
Christos Sachpekidis: University Hospital Heidelberg
Gunhild Mechtersheimer: Heidelberg University Hospital
Uwe Haberkorn: University Hospital Heidelberg
Antonia Dimitrakopoulou-Strauss: University Hospital Heidelberg
Philipp Reichert: Heidelberg University Hospital
Bart Barlogie: University of Arkansas for Medical Sciences
Carsten Müller-Tidow: Heidelberg University Hospital
Hartmut Goldschmidt: Heidelberg University Hospital
Jens Hillengass: Roswell Park Comprehensive Cancer Center
Leo Rasche: University of Arkansas for Medical Sciences
Simon F. Haas: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Frits Rhee: University of Arkansas for Medical Sciences
Karsten Rippe: German Cancer Research Center (DKFZ) and BioQuant
Marc S. Raab: Heidelberg University Hospital
Sandra Sauer: Heidelberg University Hospital
Niels Weinhold: Heidelberg University Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.

Date: 2023
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DOI: 10.1038/s41467-023-40584-4

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