Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis

Zhang, Yun; Donaher, Joana Liu; Das, Sunny; Li, Xin; Reinhardt, Ferenc; Krall, Jordan A.; Lambert, Arthur W.; Thiru, Prathapan; Keys, Heather R.; Khan, Mehreen Ali; Hofree, Matan; Wilson, Molly M.; Yedier-Bayram, Ozlem; Lack, Nathan A.; Önder, Tamer T.; Bagcı-Önder, Tugba; Tyler, Michael; Tirosh, Itay; Regev, Aviv; Lees, Jacqueline A.; Weinberg, Robert A.

doi:10.1038/s41556-022-00877-0

Cited by 78 publications

(90 citation statements)

References 67 publications

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“…Long-term treatment with a Wnt agonist would direct the equilibrium towards the plastic-dormant state, without affecting the cell-state itself. This is supported by reports of similar phenotype transitions caused by long-term in vitro treatments or targeted genetic manipulation of signalling pathways 36,37 . However, such state-transitions were also reported to occur spontaneously and were found to be a pre-requisite for metastatic outgrowth 38 .…”

Section: Discussionsupporting

confidence: 65%

Lung endothelium instructs dormancy of susceptible metastatic tumour cells

Jakab

Lee

Uvarovskii

et al. 2022

Preprint

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During metastasis, cancer cells hijack blood vessels and travel via the circulation to colonize distant sites. Due to the rarity of these events, the immediate cell fate decisions of arrested circulating tumour cells (aCTC) are poorly understood and the role of the endothelium, as the interface of dissemination, remains elusive. Here, we developed a novel strategy to specifically enrich for aCTC subpopulations capturing all cell states of the extravasation process and, in combination with single cell RNA-sequencing, provide a first blueprint of the transcriptional basis of early aCTC decisions. Upon their arrest at the metastatic site, tumour cells either started proliferating intravascularly or extravasated and preferably reached a state of quiescence. Endothelial-derived angiocrine Wnt factors were found to drive this bifurcation by inducing a mesenchymal-like phenotype in aCTCs instructing them to follow the extravasation-dormancy branch. Surprisingly, homogenous tumour cell pools showed an unexpected baseline heterogeneity in Wnt signalling activity and epithelial-to-mesenchyme-transition (EMT) states. This heterogeneity was established at the epigenetic level and served as the driving force of aCTC behaviour. Hypomethylation enabled high baseline Wnt and EMT activity in tumour cells leading them to preferably follow the extravasation-dormancy route, whereas methylated tumour cells had low activity and proliferated intravascularly. The data identify the pre-determined methylation status of disseminated tumour cells as a key regulator of aCTC behaviour in the metastatic niche. While metastatic niche-derived factors per default instruct the acquisition of quiescence, aCTCs unwind a default proliferation program and only deviate from it if hypomethylation in key gene families renders them responsive towards the microenvironment.

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Section: Discussionsupporting

confidence: 65%

Lung endothelium instructs dormancy of susceptible metastatic tumour cells

Jakab

Lee

Uvarovskii

et al. 2022

Preprint

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“…Yet it remains to be determined what exactly triggers its activation. BRCA1 itself has recently been identified as a guardian of the epithelial states (Zhang et al 2022) - inactivation of BRCA1 by CRISPR leads to increased EMP in mammary cells. Another trigger of EMT could also be senescence - itself induced by extensive genomic rearrangements following Trp53 and Brca1 deletion.…”

Section: Discussionmentioning

confidence: 99%

Luminal progenitors undergo partial epithelial-to-mesenchymal transition at the onset of basal-like breast tumorigenesis

Landragin

Saichi

Prompsy

et al. 2022

Preprint

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Defects in double-strand repair mechanisms - both through germline or somatic inactivation of repair genes - is a hallmark of basal-like breast cancers. In this genetically-unstable context, a recurrent shift in cell identity occurs within the mammary epithelium. Basal-like tumors have indeed been proposed to originate from luminal progenitor (LP) cells yet tumor-initiating events remain poorly understood. Here, we map state transitions at the onset of basal-like tumorigenesis, using a Brca-1 deficient mouse model launching tumorigenesis in multiple LP cells. Combining single-cell transcriptomics to spatial multiplex imaging, we identify a population of cycling p16- expressing cells, emerging from the luminal progenitor compartment, undergoing partial epithelial-to-mesenchymal transition and losing luminal identity. Pseudo- temporal analyses position these cells as a transitory state between aberrant Brca1deficient luminal progenitors and growing tumor cells. Concomitant to p16 activation, we show that LP cells undergo an epigenomic crisis attested by the general re-organization of their heterochromatin. They accumulate multiple H3K27me3 micro- foci - reminiscent of the formation of senescenceassociated heterochromatin foci (SAHFs) - and lose their inactive X (Xi). Both p16 activation and heterochromatin reorganization are hallmarks of human basal-like breast tumors; we propose that these events occur during initial LP transformation and are scars of an initial transitory senescent-like state.

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“…In contrast, a spectrum of hybrid epithelial–mesenchymal (hybrid E/M) cells, such as quasi-epithelial cells and quasi-mesenchymal cells, express both epithelial and mesenchymal markers and show intermediate phenotypes. Single-cell analyses of EMT processes have revealed that hybrid E/M cells go through sequential and parallel trajectories caused by context-dependent EMT signaling, chromatin modulation and transcriptional effects [ 41 , 42 ]. SNAI1 (Snail), SNAI2 (Slug), TWIST1, ZEB1 (zinc finger E-box binding homeobox 1) and ZEB2 are key transcription factors that reprogram epithelial cells toward hybrid E/M cells and mesenchymal cells under the control of WNT, FGF, Hedgehog, Notch, TGFβ and other signaling cascades ( Figure 3 ).…”

Section: Epithelial–mesenchymal Plasticitymentioning

confidence: 99%

WNT signaling and cancer stemness

Katoh

2022

Essays in Biochemistry

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Cancer stemness, defined as the self-renewal and tumor-initiation potential of cancer stem cells (CSCs), is a cancer biology property featuring activation of CSC signaling networks. Canonical WNT signaling through Frizzled and LRP5/6 receptors is transmitted to the β-catenin-TCF/LEF-dependent transcription machinery to up-regulate MYC, CCND1, LGR5, SNAI1, IFNG, CCL28, CD274 (PD-L1) and other target genes. Canonical WNT signaling causes expansion of rapidly cycling CSCs and modulates both immune surveillance and immune tolerance. In contrast, noncanonical WNT signaling through Frizzled or the ROR1/2 receptors is transmitted to phospholipase C, Rac1 and RhoA to control transcriptional outputs mediated by NFAT, AP-1 and YAP-TEAD, respectively. Noncanonical WNT signaling supports maintenance of slowly cycling, quiescent or dormant CSCs and promotes epithelial–mesenchymal transition via crosstalk with TGFβ (transforming growth factor-β) signaling cascades, while the TGFβ signaling network induces immune evasion. The WNT signaling network orchestrates the functions of cancer-associated fibroblasts, endothelial cells and immune cells in the tumor microenvironment and fine-tunes stemness in human cancers, such as breast, colorectal, gastric and lung cancers. Here, WNT-related cancer stemness features, including proliferation/dormancy plasticity, epithelial–mesenchymal plasticity and immune-landscape plasticity, will be discussed. Porcupine inhibitors, β-catenin protein–protein interaction inhibitors, β-catenin proteolysis targeting chimeras, ROR1 inhibitors and ROR1-targeted biologics are investigational drugs targeting WNT signaling cascades. Mechanisms of cancer plasticity regulated by the WNT signaling network are promising targets for therapeutic intervention; however, further understanding of context-dependent reprogramming trajectories might be necessary to optimize the clinical benefits of WNT-targeted monotherapy and applied combination therapy for patients with cancer.

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Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis

Cited by 78 publications

References 67 publications

Lung endothelium instructs dormancy of susceptible metastatic tumour cells

Lung endothelium instructs dormancy of susceptible metastatic tumour cells

Luminal progenitors undergo partial epithelial-to-mesenchymal transition at the onset of basal-like breast tumorigenesis

WNT signaling and cancer stemness

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