Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Quinn, Jeffrey J.; Jones, Matthew G.; Okimoto, Ross A.; Nanjo, Shigeki; Chan, M.K.; Yosef, Nir; Bivona, Trever G.; Weissman, Jonathan S.

doi:10.1126/science.abc1944

Cited by 190 publications

(121 citation statements)

References 103 publications

(112 reference statements)

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“…Metastatic progression is a dynamic and highly drug-resistant process. While early metastatic seeding can take place before the primary tumor is clinically detectable, the primary tumor continuously sheds metastatic cells into the circulation that can form metastases at other sites ( Quinn et al, 2021 ; Kim et al, 2009 ; Gupta and Massagué, 2006 ). Therefore, an anti-metastatic treatment that slows down this dynamic spread would have therapeutic benefit even at a late stage of disease.…”

Section: Discussionmentioning

confidence: 99%

Limited inhibition of multiple nodes in a driver network blocks metastasis

Yesilkanal

Yang

Valdespino

et al. 2021

eLife

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Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment.

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Section: Discussionmentioning

confidence: 99%

Limited inhibition of multiple nodes in a driver network blocks metastasis

Yesilkanal

Yang

Valdespino

et al. 2021

eLife

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“…Capturing signaling in individual normal cells by single-cell transcriptomics immediately after induction of different oncogenic Kras mutations may provide a platform to interrogate this model. Further, application of CRISPR-Cas9-based barcoding tools that allow simultaneous lineage tracing and transcriptome analysis of individual cells within a tumor ( Bowling et al, 2020 ; Quinn et al, 2021 ) could provide a clearer picture of the signaling dynamics throughout the course of tumor evolution.…”

Section: Discussionmentioning

confidence: 99%

Signaling levels mold the RAS mutation tropism of urethane

Counter

2021

eLife

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RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a ‘tropism’ towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity, suggesting a relationship between oncoprotein activity and RAS mutation tropism. Here, we show that changing rare codons to common in the murine Kras gene to increase protein expression shifts tumors induced by the carcinogen urethane from arising from canonical Q61 to biochemically less active G12 Kras driver mutations, despite the carcinogen still being biased towards generating Q61 mutations. Conversely, inactivating the tumor suppressor p53 to blunt oncogenic stress partially reversed this effect, restoring Q61 mutations. One interpretation of these findings is that the RAS mutation tropism of urethane arises from selection in normal cells for specific mutations that impart a narrow window of signaling that promotes proliferation without causing oncogenic stress.

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“…Taking all these factors into consideration, it is likely that the potential epigenetic heterogeneity within the tumour tissues and their derivative cell lines had some impact on DNA methylation patterns. To fully evaluate this effect would require using methods such as single-cell lineage tracing [ 54 , 55 ] or bioinformatic deconvolution [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

Rodger

Almomani

Ludgate

et al. 2021

Cancers

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DNA methylation is a heritable epigenetic mark that is fundamental to mammalian development. Aberrant DNA methylation is an epigenetic hallmark of cancer cells. Cell lines are a critical in vitro model and very widely used to unravel mechanisms of cancer cell biology. However, limited data are available to assess whether DNA methylation patterns in tissues are retained when cell lines are established. Here, we provide the first genome-scale sequencing-based methylation map of metastatic melanoma tumour tissues and their derivative cell lines. We show that DNA methylation profiles are globally conserved in vitro compared to the tumour tissue of origin. However, we identify sites that are consistently hypermethylated in cell lines compared to their tumour tissue of origin. The genes associated with these common differentially methylated regions are involved in cell metabolism, cell cycle and apoptosis and are also strongly enriched for the H3K27me3 histone mark and PRC2 complex-related genes. Our data indicate that although global methylation patterns are similar between tissues and cell lines, there are site-specific epigenomic differences that could potentially impact gene expression. Our work provides a valuable resource for identifying false positives due to cell culture and for better interpretation of cancer epigenetics studies in the future.

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Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Cited by 190 publications

References 103 publications

Limited inhibition of multiple nodes in a driver network blocks metastasis

Limited inhibition of multiple nodes in a driver network blocks metastasis

Signaling levels mold the RAS mutation tropism of urethane

Comparison of Global DNA Methylation Patterns in Human Melanoma Tissues and Their Derivative Cell Lines

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