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Abstract

Since the dawn of multicellular life, cells have diversified through the differentiation of functionally distinct cell types. These cell types give rise to different cancer types and subtypes, with cell of origin central to intertumor heterogeneity. For example, B-cell non-Hodgkin lymphomas are tied to distinct stages of B-cell maturation. In contrast, intratumor heterogeneity, intrinsic to cancer evolution and treatment response, is typically considered distinct from cell-type differentiation. In this thesis, I challenged this view by investigating whether cell-type differentiation influences intratumor heterogeneity in B-cell lymphomas.

Through joint single-cell transcriptomic and surface epitope profiling of diffuse large B-cell (DLBCL), mantle cell (MCL), follicular (FL), and marginal zone (MZL) lymphomas from 43 patients, alongside 8 reactive lymph nodes, I found that individual tumors were comprised of multiple B-cell maturation states, suggesting ongoing differentiation from the cell of origin. Tumor maturation state composition varied across and within lymphoma entities, blurring entity boundaries. Cell-of-origin classifiers revealed the presence of mixed germinal center (GCB) and activated B-cell (ABC) clinical subtypes within DLBCL and FL tumors. Varying tumor maturation state composition over time indicates tumors evolve through differentiation, maintained by differentially active maturation transcription factors observed between tumor maturation states. Highly multiplexed immunohistochemistry revealed intratumor maturation states occupy distinct spatial niches, differing in immune infiltration while maintaining maturation-associated cellular interactions. Intratumor maturation states were subject to copy number variation and showed varying expression patterns of mutated genes, suggesting that differentiation and genetic variation are interconnected in cancer.

My findings put forward a model of tumor evolution in which cancer cells achieve diversification through cell-type differentiation. Mutability of cell types in cancer poses challenges and opportunities for cancer diagnosis, whereby tumors are not tied to their cell of origin, and cancer treatment, which may need to account for diverse and evolving spectra of cancer cell types. These insights open a wealth of future research avenues in clonal evolution, drug resistance, and precision medicine across cancers.