A single-cell multi-omic and spatial atlas of B cell lymphomas reveals differentiation drives intratumor heterogeneity

Author:

Fitzgerald DonnachaORCID,Roider TobiasORCID,Baertsch Marc-AndreaORCID,Kibler ArturORCID,Horlova Anastasiia,Chung Erin,Vöhringer Harald,Mathioudaki AnnaORCID,Budeus Bettina,Passerini VerenaORCID,Knoll Mareike,Mammen JohannesORCID,Li Linsha,Caillé Léandra,Czernilofsky FelixORCID,Bruch Peter-MartinORCID,Liebers Nora,Meyer-Bender MatthiasORCID,Weigert OliverORCID,Zaugg JudithORCID,Nolan GarryORCID,Seifert MarcORCID,Dietrich SaschaORCID,Huber WolfgangORCID

Abstract

SummaryIntratumor heterogeneity is intrinsic to cancer evolution and treatment resistance, although it is typically considered distinct from the differentiation processes driving cell-type and cancer-type diversity. Nodal B cell non-Hodgkin lymphomas are tied to distinct stages of B cell maturation. Through a single-cell multi-omic and spatial atlas of diffuse large B cell, mantle cell, follicular, and marginal zone lymphomas in addition to reactive lymph nodes in 51 patients, we uncovered co-existing B cell maturation states within the same tumors. These intratumor maturation states emerged from the same clone, revealing ongoing differentiation from the cell-of-origin. Maturation state composition varied across and within disease entities, with tumors encompassing mixed cell-of-origin clinical subtypes. Intratumor maturation states inhabited unique spatial niches, maintaining their maturation-associated cellular interactions and regulatory networks while harboring distinct genetic variant expression patterns. Our findings show that cell-type differentiation remains plastic in cancer and is central to tumor variation and evolution.Graphical abstract

Publisher

Cold Spring Harbor Laboratory

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