Non-genetic determinants of malignant clonal fitness at single-cell resolution

Fennell, Katie; Vassiliadis, Dane; Lam, Enid Y.N.; Martelotto, Luciano G.; Balic, Jesse J.; Hollizeck, Sebastian; Weber, Tom S.; Semple, Timothy; Wang, Qing; Miles, Denise C.; MacPherson, Laura; Chan, Yih-Chih; Guirguis, Andrew A.; Kats, Lev; Wong, Emily S.; Dawson, Sarah‐Jane; Naik, Shalin H.; Dawson, Mark A.

doi:10.1038/s41586-021-04206-7

Cited by 84 publications

(103 citation statements)

References 45 publications

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“…2, G and H ). Some highly expressed interclonally differentially expressed genes were previously identified as heritably maintained in short-term cultures of transformed cell lines and in cancer clones in vivo ( 8, 21 ).…”

Section: Mainmentioning

confidence: 99%

Clonally heritable gene expression imparts a layer of diversity within cell types

Mold

Weissman

Ratz

et al. 2022

Preprint

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Cell types can be classified based on shared patterns of transcription. Variability in gene expression between individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. We asked whether long-term, heritable differences in transcription can impart diversity within a cell type. Studying clonal human lymphocytes and mouse brain cells, we uncover a vast diversity of heritable transcriptional states among different clones of cells of the same type in vivo. In lymphocytes we show that this diversity is coupled to clone specific chromatin accessibility, resulting in distinct expression of genes by different clones. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging and disease.

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Section: Mainmentioning

confidence: 99%

Clonally heritable gene expression imparts a layer of diversity within cell types

Mold

Weissman

Ratz

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Diversified and labile transcriptional programs within a heterogenous tumor cell population can rapidly confer clonal fitness in the face of therapeutic pressure (Bolis et al, 2021; Davies et al, 2021; Fennell et al, 2021; Taavitsainen et al, 2021). In our models clonally-determined lineage distributions were partially explained by pre-existing genomic alterations.…”

Section: Discussionmentioning

confidence: 99%

“…These lineage-plastic subtypes of mCRPC are not static or homogeneous - multiple subpopulations can exist in a patient tumor, yet the dynamic relationship of the subpopulation structure is not well understood (Cejas et al, 2021; Labrecque et al, 2019). Epigenetic mechanisms underlying lineage-plasticity in cancer can instill resistance without genetic clonal selection (Fennell et al, 2021) and minor subpopulations that are not easily detected in bulk may command an outsized role in growth and resistance (Sharma et al, 2010). Distinct hierarchical phenotypes existing at variable frequencies within a tumor often respond differently to the selective pressure of a given treatment (Sharma et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The origin and dynamics of cellular heterogeneity vary across lineage subtypes of castrate resistant prostate cancer

Beshiri

Capaldo

Lake

et al. 2022

Preprint

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To resist lineage-dependent therapies, cancer cells adopt a plastic stem-like state, leading to phenotypic heterogeneity. Here we dissect the cellular origins of such heterogeneity in a metastatic castration-resistant prostate cancer (CRPC) patient-derived adenocarcinoma organoid model displaying a range of luminal and neuroendocrine phenotypes and driven by mutations in cell cycle (CDKN1B) and epigenetic (ARID1A, and ARID1B) regulators. As shown by lineage tracing, metastatic tumor heterogeneity originated from distinct subclones of infrequent stem/progenitor cells that each produced a full distribution of differentiated lineage markers, suggesting multiclonal evolution to a relatively stable bipotential state. Single cell ATAC-seq analyses revealed the co-occurrence of transcription factor activities associated with multiple disparate lineages in the stem/progenitors: WNT and RXR stem factors, AR and FOXA1 luminal epithelial drivers, and NR2F1 and ASCL1 neural factors. Inhibition of AR in combination with AURKA but not EZH2 blocked tumor growth. These data provide insight into the origins and dynamics of cancer cell plasticity and stem targeted therapy.

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“…Since cancer evolution constitutes a formidable obstacle to successful treatment, further studies to unravel the evolutionary processes of tumor cells are required and already arising [49]. Integrating data from transcriptomes, genomes, and posttranslational modifications - best on single-cell level and within the same individual – should provide a better overall picture of tumor evolution.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal-epithelial transition in lymph node metastases of oral squamous cell carcinoma is accompanied by ZEB1 expression

Horny

Sproll

Peiffer

et al. 2022

Preprint

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Oral cavity squamous cell carcinomas (OSCC) that spread to the regional lymph nodes are associated with a high degree of epithelial-mesenchymal plasticity (EMP). Here, RNA sequencing of 1,946 carcinoma and 2,175 stromal cells of an advanced metachronous OSCC lymph node metastasis revealed heterogeneity of the OSCC cells with respect to epithelial-mesenchymal transition (EMT) states, metabolic adaptations, and cell cycle. Seven cell clusters formed a branching trajectory with epithelial differentiation, partial EMT states and metabolic adaptations. Notably, partial EMT was associated with stress response, especially with HSPA upregulation, immune-modulation through CXCL14 and a higher fraction of proliferating cells, whereas epithelial differentiation correlated with higher cytokeratin and kallikrein expression. While EMP-associated transcription factors SNAI2 and ZEB1 were active in all cancer cells, TWIST1, SNAI1 and ZEB1 activity were more pronounced in the epithelial branch. Epithelial differentiating cells have less receptor-ligand interactions with stromal cells than partial EMT cells indicating a more independent regulation. Interestingly, cells in and close to the trunk of the trajectory adapt to hypoxic and hypoglycemic conditions expressing genes related to glycolytic and amino acid catabolism. Our work provides in-depth insights into phenotypic heterogeneity within an OSCC lymph node metastasis, specifically how EMP drives locoregional progression.

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Non-genetic determinants of malignant clonal fitness at single-cell resolution

Cited by 84 publications

References 45 publications

Clonally heritable gene expression imparts a layer of diversity within cell types

Clonally heritable gene expression imparts a layer of diversity within cell types

The origin and dynamics of cellular heterogeneity vary across lineage subtypes of castrate resistant prostate cancer

Mesenchymal-epithelial transition in lymph node metastases of oral squamous cell carcinoma is accompanied by ZEB1 expression

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