Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states

Simeonov, Kamen P.; Byrns, China N.; Clark, Megan L.; Norgard, Robert J.; Martin, Beth; Stanger, Ben Z.; Shendure, Jay; McKenna, Aaron; Lengner, Christopher J.

doi:10.1016/j.ccell.2021.05.005

Cited by 179 publications

(139 citation statements)

References 66 publications

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“…As in the present single-cell data, the transcription of metastatic cancer cells is consistent with that of their primary cancer cells. Two recent studies on Sc-RNA seq sequencing and lineage tracing show that cancer cells pre-metastasis have partial EMT ( 7 ) or hybrid EMT state ( 24 ), suggesting that metastatic cancer cells have their own reversible EMT genetic program. At the same time, in this single-cell data, the ecosystem of metastatic cancer, which is different from that of primary cancer cells, contributes to immunosuppression and stromal environment of pro-metastasis, indicating that it assists the transcriptomic expression of metastatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomic Analysis of Ecosystems in Papillary Thyroid Carcinoma Progression

et al. 2021

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BackgroundDespite extensive research, the papillary thyroid carcinoma (PTC) ecosystem is poorly characterized and, in particular, locoregional progression. Available evidence supports that single-cell transcriptome sequencing (Sc-RNA seq) can dissect tumor ecosystems.MethodsTissue samples from one PTC patient, including matched primary tumor (Ca), lymph node (LN) metastasis, and paracancerous tissue (PCa), were subjected to Sc-RNA seq with 10×Genomics. Dual-label immunofluorescence and immunohistochemistry were used to confirm the existence of cell subtypes in a separate cohort.Results11,805 cell transcriptomes were profiled, cell landscapes of PTC were composed of malignant follicular epithelial cells (MFECs), CD8+ and CD4+ T cells, B cells, vascular endothelial cells, fibroblasts and cancer-associated fibroblasts (CAFs). Between Ca and LN ecosystems, the proportions of MFEC and interstitial cells were similar, less than 1/25(229/6,694, 361/3,895), while the proportion of normal follicular epithelial cells (NFECs) and interstitial cells was > 2 in PCa (455/171). NFECs in PCa formed a separate cluster, while MFECs in Ca and LN exhibited a profound transcriptional overlap, and the interstitial cells among these samples had an overall concordance in their identity and representation, albeit with some distinctions in terms of the cell percentage per subset. A fraction of the B cell subpopulation in Ca expressed inhibitory receptors, while their respective ligand genes were clearly transcribed in T cell and malignant epithelial cell clusters, while some CD8+ T cells in both Ca and LN produced high levels of inhibitory receptors whose respective ligands were overexpressed in some CD4+ T cells. Three CAF subtypes in Ca and LN were identified, which may be due to mutual transitions.ConclusionsOur data provide new insights into the PTC ecosystem and highlight the differences in ecosystems in PTC progression, which updates our understanding of PTC biology and will improve individualized patient treatment.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomic Analysis of Ecosystems in Papillary Thyroid Carcinoma Progression

et al. 2021

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“…Recent preclinical and clinical observations have suggested high metastatic potential of hybrid E/M phenotypes, and their association with worse patient survival across cancer types (Bierie et al, 2017;Godin et al, 2020;Huang et al, 2013;Kröger et al, 2019;Pastushenko and Blanpain, 2019;Puram et al, 2017;Sahoo et al, 2021b;Simeonov et al, 2021). Hybrid E/M phenotypes have also been observed in circulating tumor cells (CTCs); their higher frequency is often concomitant with worse clinicopathological features (Bocci et al, 2021;Lecharpentier et al, 2011;Saxena et al, 2019;Yu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts

Mandal

Tejaswi

Janivara

et al. 2021

Preprint

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Epithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient prognosis. Here, we compare three distinct transcriptomic-based metrics - each derived using a different gene list and algorithm - that quantify the EMP spectrum. Our results for 96 cancer-related RNA-seq datasets reveal a high degree of concordance among these metrics in quantifying the extent of EMP. Moreover, each metric, despite being trained on cancer expression profiles, recapitulates the expected changes in EMP scores for non-cancer contexts such as lung fibrosis and cellular reprogramming into induced pluripotent stem cells. Thus, we offer a scoring platform to quantify the extent of EMP in vitro and in vivo for diverse biological applications including cancer.

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“…Indeed, it has been reported that cells with hEMT features give rise to daughter cells that are either mesenchymal or epithelial 54,36 , are more prone to migrate and promote the formation of circulating tumour cells 37 . Moreover, stable late hEMT states have been linked with maximal metastatic potential and worse overall survival 55 , explaining the variable metastatic potential we observed in cell lines in the context of hEMT. Undoubtedly, the hEMT state can be further subdivided into sub-states, as shown by Goetz et al 4 , Brown et al 56 and also by us in the tissue-specific analyses.…”

Section: Discussionmentioning

confidence: 81%

Genomic events shaping epithelial-to-mesenchymal trajectories in cancer

Tagliazucchi

Secrier

2021

Preprint

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The epithelial to mesenchymal transition (EMT) is a key cellular process underlying cancer progression, with multiple intermediate states whose molecular hallmarks remain poorly characterized. To fill this gap, we explored EMT trajectories in 8,778 tumours of epithelial origin and identified three macro-states with prognostic and therapeutic value, attributable to epithelial, hybrid E/M (hEMT) and mesenchymal phenotypes. We show that the hEMT state is remarkably stable and linked with increased aneuploidy, APOBEC mutagenesis and hypoxia. Additionally, we provide an extensive catalogue of genomic events underlying distinct evolutionary constraints on EMT transformation, including novel pan-cancer dependencies of hEMT on driver genes PRRX1, BCOR and CNOT3, as well as links between full mesenchymal transformation and REG3A and SHISA4 mutations in lung and breast cancers, respectively. This study sheds light on the aetiology of the lesser characterised hybrid E/M state in cancer progression and the broader genomic hallmarks shaping the mesenchymal transformation of primary tumours.

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Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states

Cited by 179 publications

References 66 publications

Single-Cell Transcriptomic Analysis of Ecosystems in Papillary Thyroid Carcinoma Progression

Single-Cell Transcriptomic Analysis of Ecosystems in Papillary Thyroid Carcinoma Progression

Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts

Genomic events shaping epithelial-to-mesenchymal trajectories in cancer

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