BRN 2 Invade

Pathria, Gaurav; Ronai, Ze’ev

doi:10.1016/j.ccell.2018.06.010

Cited by 4 publications

(8 citation statements)

References 10 publications

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“…Our previous studies have established a central role of osteogenic cells (the cells in the osteogenic lineage from MSCs to newly developed osteoblasts) in early-stage bone colonization 12 , 13 . These cells constitute the osteogenic niche and support cancer cell proliferation through adherens junctions and gap junctions.…”

Section: Resultsmentioning

confidence: 99%

“…To examine cancer cell specificity related to MBT, we tested several more human and murine cancer cell lines known to establish bone metastases according to previous studies, namely 4T1, 4T1.2, AT3, and SCP28 13 , 14 . All of these lines exhibited similar MBT properties (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Bone micrometastases develop heterotypic adherens junctions (hAJs) and gap junctions (GJs) with osteogenic cells when they are in full contact 12 , 13 . Here, we asked whether the physical contact between DSLS and osteogenic cells is also mediated via hAJs and GJs, before more extensive cancer-osteogenic cell contact is established.…”

Section: Resultsmentioning

confidence: 99%

“…Adherens junctions often precede the development of, and can stabilize GJs, which allow direct substance diffusion between the contacting cells 31 – 33 . Connexin 43 (Cx43), a major component of GJ in bone micrometastases 13 , was expressed at the interface between DSLS and osteogenic cells (Fig. 4c ).…”

Section: Resultsmentioning

confidence: 99%

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Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

et al. 2020

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Migration and invasion are key properties of metastatic cancer cells. These properties can be acquired through intrinsic reprogramming processes such as epithelial-mesenchymal transition. In this study, we discovered an alternative “migration-by-tethering” mechanism through which cancer cells gain the momentum to migrate by adhering to mesenchymal stem cells or osteoblasts. This tethering is mediated by both heterotypic adherens junctions and gap junctions, and leads to a unique cellular protrusion supported by cofilin-coated actin filaments. Inhibition of gap junctions or depletion of cofilin reduces migration-by-tethering. We observed evidence of these protrusions in bone segments harboring experimental and spontaneous bone metastasis in animal models. These data exemplify how cancer cells may acquire migratory ability without intrinsic reprogramming. Furthermore, given the important roles of osteogenic cells in early-stage bone colonization, our observations raise the possibility that migration-by-tethering may drive the relocation of disseminated tumor cells between different niches in the bone microenvironment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

et al. 2020

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“…Predicted and validated 5 CDK12 loss-of-function (LOF) point mutations and deletions have been recurrently identified in prostate 27,28 and ovarian 29,30 tumors. RNA sequencing data from ovarian serous adenocarcinoma 29 and prostate adenocarcinoma 27 patient tumors showed that putative CDK12 LOF mutations, but not oncogenic mutations in other BRCAness genes, increased IPA usage within key BRCAness genes, including ATM, WRN, and FANCD2, compared to tumors that were wild type for CDK12 (Fig.…”

mentioning

confidence: 99%

CDK12 regulates DNA repair genes by suppressing intronic polyadenylation

Dubbury

Boutz

Sharp

2018

Nature

215

224

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Mutations that attenuate homologous recombination (HR) repair promote tumorigenesis and sensitize cells to chemotherapeutics that cause replication fork collapse, a phenotype known as “BRCAness.” 1 BRCAness tumors arise from loss-of-function mutations in 22 genes. 1 Of these genes, all but one (Cdk12) directly function in the HR repair pathway. 1 Cdk12 phosphorylates Serine 2 of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) heptapeptide repeat, 2 – 7 a modification that regulates transcription elongation, splicing, and cleavage/polyadenylation. 8 , 9 Genome-wide expression studies suggest that Cdk12 depletion abrogates the expression of several HR genes relatively specifically, blunting HR repair. 3 – 7 , 10 , 11 This observation suggests that Cdk12 mutational status may predict sensitivity to targeted treatments against BRCAness, such as Parp1 inhibitors, and that Cdk12 inhibitors may induce sensitization of HR-competent tumors to these treatments. 6 , 7 , 10 , 11 Despite growing clinical interest, the mechanism by which Cdk12 regulates HR genes remains unknown. Here we find that Cdk12 globally suppresses intronic polyadenylation events, enabling the production of full-length gene products. Many HR genes harbor more intronic polyadenylation sites than other expressed genes, and these sites are particularly sensitive to Cdk12 loss. The cumulative effect of these sites accounts for the enhanced sensitivity of HR gene expression to Cdk12 loss, and we find that this mechanism is conserved in human tumors harboring Cdk12 loss-of-function mutations. This work clarifies the function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumor biomarker.

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HoxA9 binds and represses the Cebpa +8 kb enhancer

Peng

Guo

et al. 2019

PLoS ONE

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C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav -NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav- NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9.

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BRN 2 Invade

Cited by 4 publications

References 10 publications

Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

CDK12 regulates DNA repair genes by suppressing intronic polyadenylation

HoxA9 binds and represses the Cebpa +8 kb enhancer

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