Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

Fumagalli, Arianna; Oost, Koen C.; Kester, Lennart; Morgner, Jessica; Bornes, Laura; Bruens, Lotte; Spaargaren, Lisa; Azkanaz, Maria; Schelfhorst, Tim; Beerling, Evelyne; Heinz, Maria C.; Postrach, Daniel; Seinstra, Daniëlle; Sieuwerts, Anieta M.; Martens, John W.M.; Elst, Stefan van der; Baalen, Martijn v.; Bhowmick, Debashis; Vrisekoop, Nienke; Ellenbroek, Saskia I.J.; Suijkerbuijk, Saskia J.E.; Snippert, Hugo J.G.; Rheenen, Jacco van

doi:10.1016/j.stem.2020.02.008

Cited by 229 publications

(226 citation statements)

References 56 publications

(76 reference statements)

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“…Stem cells, often defined as a pool of cells sustained at the apex of cell hierarchies or developmental trajectories, are traditionally seen as unique drivers of tissue homeostasis and regeneration of normal tissue, but also of metastasis and therapy-resistance in cancer 52 . However, recent studies have shown metastasis and stemness can be uncoupled in colorectal cancer metastasis 53 , and that oncogenic mutations and paracrine signals can reverse developmental trajectories so that more differentiated cells can regain stem cell characteristics [54][55][56] . Here, we show that a gradient of ERK target gene expression is associated with developmental latent time in CRC organoids, extending our previous finding of graded ERK activity in CRC organoids 57 .…”

Section: Mapk Target Gene Expression Defines Crc Differentiation Statesmentioning

confidence: 99%

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

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In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue. To define differences in cellular composition between the normal colon and colorectal cancer, and to map potential cellular interactions between tumor cells and their microenvironment, we profiled transcriptomes of >50,000 single cells from tumors and matched normal tissues of eight colorectal cancer patients. We find that tumor formation is accompanied by changes in epithelial, immune and stromal cell compartments in all patients. In the epithelium, we identify a continuum of five tumor-specific stem cell and progenitor-like populations, and persistent multilineage differentiation. We find multiple stromal and immune cell types to be consistently expanded in tumor compared to the normal colon, including cancer-associated fibroblasts, pericytes, monocytes, macrophages and a subset of T cells. We identify epithelial tumor cells and cancer-associated fibroblasts as relevant for assigning colorectal cancer consensus molecular subtypes. Our survey of growth factors in the tumor microenvironment identifies cell types responsible for increased paracrine EGFR, MET and TGF-β signaling in tumor tissue compared to the normal colon.We show that matched colorectal cancer organoids retain cell type heterogeneity, allowing to define a distinct differentiation trajectory encompassing stem and progenitor-like tumor cells. In summary, our single-cell analyses provide insights into cell types and signals shaping colorectal cancer cell plasticity.

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Section: Mapk Target Gene Expression Defines Crc Differentiation Statesmentioning

confidence: 99%

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

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“…Moreover, a recent study reported that acute promyelocytic leukemia cells undergoing differentiation driven by retinoic acid could re-acquire the LIC state following chemotherapy withdrawal, effectively reversing the differentiation trajectory (McKenzie et al, 2019). Extending this concept to solid tumors, a similar effect was recently uncovered in colon cancer, where cells devoid of the stem cell marker Lgr5 can establish metastases and give rise to Lgr5 + cancer stem cells (Fumagalli et al, 2020). These findings parallel the known phenomenon that in healthy tissues, adult stem cell identity can be plastic: professional stem cells maintain tissue integrity at steady state, but under stress, facultative stem cells can be recruited from apparently lineage-committed populations (Raven et al, 2017;Tata et al, 2013).…”

Section: Discussionmentioning

confidence: 93%

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

Morris

Marion

Hughes

et al. 2020

Preprint

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Leukemia initiating cells (LICs) fuel leukemic growth and spark relapse. Previously thought to be primitive and rare, the LIC state may actually be heterogeneous and dynamic, enabling evasion of therapies. Here, we use single-cell transcriptomics to dissect the ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL).Although we identify rare transcriptionally and phenotypically primitive LICs, we also observe LICs emerging from more differentiated populations with the capability to replenish the full cellular diversity of MLL-r B-ALL. We find that activation of MYC-driven oxidative phosphorylation controls this process of LIC state conversion.

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“…Certainly, Fumagalli and colleagues observed most disseminated CRC cells in circulation to be LGR5 negative. Latter cells formed distant metastases in which CSC appeared LGR5 positive [ 54 ]. This plasticity of CCSC may explain the relatively low level of LGR5 , as BKZ-2 and BKZ-3 also revealed an EMT-phenotype reflected by a high level of SLUG.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

Esch

Windmöller

Hanewinkel

et al. 2020

Cancers

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Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.

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Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

Cited by 229 publications

References 56 publications

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

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