8 results on '"Erik Sahai"'
Search Results
2. The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells
- Author
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Eishu Hirata, Kojiro Ishibashi, Shinji Kohsaka, Keiko Shinjo, Shinya Kojima, Yutaka Kondo, Hiroyuki Mano, Seiji Yano, Etsuko Kiyokawa, and Erik Sahai
- Subjects
Biological Sciences ,Cell Biology ,Cancer ,Transcriptomics ,Science - Abstract
Summary: Brain metastasis is an ineffective process, and many cancer cells enter into an indolent state following extravasation in the brain. Single cell RNA sequencing of melanoma brain metastases reveals that non-proliferating brain metastatic melanoma cells exhibit a pattern of gene expression associated with inhibition of DNA methyltransferase 1 (DNMT1). The brain microenvironment, specifically the combination of reactive astrocytes and mechanically soft surroundings, suppressed DNMT1 expression in various cancer types and caused cell cycle delay. Somewhat unexpectedly, we find that DNMT1 suppression not only induces cell cycle delay but also activates pro-survival signals in brain metastatic cancer cells, including L1CAM and CRYAB. Our results demonstrate that transcriptional changes triggered by DNMT1 suppression is a key step for cancer cells to survive in the brain microenvironment and that they also restrict cancer cell proliferation. The dual consequences of DNMT1 suppression can explain the persistence of indolent cancer cells in the brain microenvironment.
- Published
- 2020
- Full Text
- View/download PDF
3. A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation
- Author
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Esther N. Arwert, Allison S. Harney, David Entenberg, Yarong Wang, Erik Sahai, Jeffrey W. Pollard, and John S. Condeelis
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Summary: Tumor-associated macrophages (TAMs) are critical for tumor metastasis. Two TAM subsets support cancer cell intravasation: migratory macrophages guide cancer cells toward blood vessels, where sessile perivascular macrophages assist their entry into the blood. However, little is known about the inter-relationship between these functionally distinct TAMs or their possible inter-conversion. We show that motile, streaming TAMs are newly arrived monocytes, recruited via CCR2 signaling, that then differentiate into the sessile perivascular macrophages. This unidirectional process is regulated by CXCL12 and CXCR4. Cancer cells induce TGF-β-dependent upregulation of CXCR4 in monocytes, while CXCL12 expressed by perivascular fibroblasts attracts these motile TAMs toward the blood vessels, bringing motile cancer cells with them. Once on the blood vessel, the migratory TAMs differentiate into perivascular macrophages, promoting vascular leakiness and intravasation. : Tumor-associated macrophages (TAMs) are essential for metastasis. Arwert et al. show that, following extravasation, monocytes initially become motile TAMs. Tumor-derived TGF-β then induces CXCR4 on TAMs, stimulating them to migrate toward CXCL12-expressing perivascular fibroblasts. Once adjacent to blood vessels, TAMs differentiate into metastasis-assisting perivascular TAMs. Keywords: tumor associated macrophages, TAMs, TGF beta, breast cancer, metastasis, CXCR4, CCR2, TMEM, Mena
- Published
- 2018
- Full Text
- View/download PDF
4. Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization
- Author
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Yaiza del Pozo Martin, Danielle Park, Anassuya Ramachandran, Luigi Ombrato, Fernando Calvo, Probir Chakravarty, Bradley Spencer-Dene, Stefanie Derzsi, Caroline S. Hill, Erik Sahai, and Ilaria Malanchi
- Subjects
Biology (General) ,QH301-705.5 - Abstract
During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization.
- Published
- 2015
- Full Text
- View/download PDF
5. Cdc42EP3/BORG2 and Septin Network Enables Mechano-transduction and the Emergence of Cancer-Associated Fibroblasts
- Author
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Fernando Calvo, Romana Ranftl, Steven Hooper, Aaron J. Farrugia, Emad Moeendarbary, Andreas Bruckbauer, Facundo Batista, Guillaume Charras, and Erik Sahai
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Cancer-associated fibroblasts (CAFs) are non-cancerous cells found in solid tumors that remodel the tumor matrix and promote cancer invasion and angiogenesis. Here, we demonstrate that Cdc42EP3/BORG2 is required for the matrix remodeling, invasion, angiogenesis, and tumor-growth-promoting abilities of CAFs. Cdc42EP3 functions by coordinating the actin and septin networks. Furthermore, depletion of SEPT2 has similar effects to those of loss of Cdc42EP3, indicating a role for the septin network in the tumor stroma. Cdc42EP3 is upregulated early in fibroblast activation and precedes the emergence of the highly contractile phenotype characteristic of CAFs. Depletion of Cdc42EP3 in normal fibroblasts prevents their activation by cancer cells. We propose that Cdc42EP3 sensitizes fibroblasts to further cues—in particular, those activating actomyosin contractility—and thereby enables the generation of the pathological activated fibroblast state.
- Published
- 2015
- Full Text
- View/download PDF
6. The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells
- Author
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Shinji Kohsaka, Hiroyuki Mano, Erik Sahai, Etsuko Kiyokawa, Eishu Hirata, Yutaka Kondo, Shinya Kojima, Seiji Yano, Kojiro Ishibashi, and Keiko Shinjo
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0301 basic medicine ,Cell ,02 engineering and technology ,Biology ,Article ,03 medical and health sciences ,medicine ,Transcriptomics ,lcsh:Science ,Cancer ,Multidisciplinary ,Melanoma ,Cell Biology ,Cell cycle ,Biological Sciences ,021001 nanoscience & nanotechnology ,medicine.disease ,Extravasation ,030104 developmental biology ,medicine.anatomical_structure ,Cancer cell ,Cancer research ,DNMT1 ,lcsh:Q ,0210 nano-technology ,Brain metastasis - Abstract
Summary Brain metastasis is an ineffective process, and many cancer cells enter into an indolent state following extravasation in the brain. Single cell RNA sequencing of melanoma brain metastases reveals that non-proliferating brain metastatic melanoma cells exhibit a pattern of gene expression associated with inhibition of DNA methyltransferase 1 (DNMT1). The brain microenvironment, specifically the combination of reactive astrocytes and mechanically soft surroundings, suppressed DNMT1 expression in various cancer types and caused cell cycle delay. Somewhat unexpectedly, we find that DNMT1 suppression not only induces cell cycle delay but also activates pro-survival signals in brain metastatic cancer cells, including L1CAM and CRYAB. Our results demonstrate that transcriptional changes triggered by DNMT1 suppression is a key step for cancer cells to survive in the brain microenvironment and that they also restrict cancer cell proliferation. The dual consequences of DNMT1 suppression can explain the persistence of indolent cancer cells in the brain microenvironment., Graphical Abstract, Highlights • Indolence of brain metastatic melanoma cells is associated with DNMT1 inhibition • Reactive astrocytes and mechanically soft surroundings suppress DNMT1 expression • DNMT1 suppression dually activates pro-survival and anti-proliferative signals • DNMT1-αB crystallin axis supports the survival of indolent brain metastatic cells, Biological Sciences; Cell Biology; Cancer; Transcriptomics
- Published
- 2020
7. Tumor Cell Migration in Three Dimensions
- Author
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John Marshall, Steven Hooper, and Erik Sahai
- Subjects
Extracellular matrix ,biology ,Laminin ,Cell culture ,biology.protein ,Tumor Cell Migration ,Motility ,Cell migration ,Cell movement ,Rho-Associated Kinases ,Cell biology - Abstract
In almost all physiological and pathological situations, cells migrate through three-dimensional environments, yet most studies of cell motility have used two-dimensional substrates. It is clear that two-dimensional substrates do not mimic the in vivo environment accurately, and recent work using three-dimensional environments has revealed many different mechanisms of cell migration (Abbott, 2003; Sahai and Marshall, 2003; Wolf et al., 2003). This chapter will describe methods for generating three-dimensional matrices suitable for studying cell motility, methods for imaging the morphology of motile cells in situ, and methods for quantifying cell migration through three-dimensional environments.
- Published
- 2006
8. Purification of TAT‐C3 Exoenzyme
- Author
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Erik Sahai and Michael F. Olson
- Subjects
Transduction (genetics) ,RHOA ,biology ,Biochemistry ,Protein family ,RHOB ,biology.protein ,RhoC ,Exoenzyme ,GTPase ,Cell morphology ,Cell biology - Abstract
The Clostridium botulinum C3 exoenzyme has been an invaluable tool for the study of the biological functions of Rho GTPases. The C3 enzyme selectively catalyzes the ADP-ribosylation, and consequent inactivation, of RhoA, RhoB, and RhoC of the Rho GTPase protein family. Through the experimental use of C3, it has been possible to determine the contributions made by these signaling proteins to processes including the regulation of cell morphology, cell cycle progression, and gene transcription. Unlike bacterial toxins that have some means to attach to and/or enter cells, C3 does not have an element that facilitates efficient entry. As a result, numerous methods have been used to effectively deliver C3 into cells. One approach has been to engineer a recombinant C3 with an HIV TAT leader sequence that permits transduction of the protein across the plasma membrane. In this chapter, the purification and characterization of the recombinant TAT-C3 protein is described.
- Published
- 2006
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