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Comparative transcriptional profiling of tumor-associated and normal lymphatic endothelial cells

ABSTRACT: In the past decade, the relevance of tumor-induced lymphangiogenesis for the metastatic spread of tumor cells has been demonstrated, thus indicating the potential of targeting tumor lymphangiogenesis to treat cancer. Whereas numerous preclinical studies demonstrated that blocking angiogenesis or lymphangiogenesis could inhibit tumor metastasis, the scarcity of highly selective targeting candidates hampers their translation to the clinic. We employed a new approach consisting of immuno-laser capture microdissection (i-LCM) and transcriptional profiling by means of microarrays in order to identify novel tumor-specific endothelial markers.

ORGANISM(S): Mus musculus

PROVIDER: GSE15760 | GEO | 2010/04/01

SECONDARY ACCESSION(S): PRJNA116791

REPOSITORIES: GEO

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Comparative transcriptional profiling of tumor-associated and normal lymphatic endothelial cells

Project description:In the past decade, the relevance of tumor-induced lymphangiogenesis for the metastatic spread of tumor cells has been demonstrated, thus indicating the potential of targeting tumor lymphangiogenesis to treat cancer. Whereas numerous preclinical studies demonstrated that blocking angiogenesis or lymphangiogenesis could inhibit tumor metastasis, the scarcity of highly selective targeting candidates hampers their translation to the clinic. We employed a new approach consisting of immuno-laser capture microdissection (i-LCM) and transcriptional profiling by means of microarrays in order to identify novel tumor-specific endothelial markers. By using short immunostainings prior to microdissection, specific identification of lymphatic (LECs) and blood (BECs) endothelial cells was allowed. For the subsequent gene expression profiling, a single round of the Ribo-Spia amplification method in combination with the Affymterix microarray platform was used. Comparison of gene expression profiles of tumor-associated and normal LECs resulted in the identification of differentially expressed genes in tumor-associated lymphatic vasculature.

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Effect of EphrinB2 on gene expression in cultured lymphatic endothelial cells (LECs) under hypoxia

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2024-10-15 | GSE273930 | GEO

Laser-capture microscopy coupled with Smart-seq2 (LCM-seq) for robust and efficient transcriptomic profiling of mouse and human tissues

Project description:Generally, when LCM is used in diverse transcriptomic analyses, several hundred, if not thousands, of cells are needed to obtain high quality of RNA-seq data. As some cellular populations are very small and tissue often in scarcity, we aimed to carefully document the lowest number of cells needed to retrieve sequencable libraries. We started with capturing 120 cells and subsequently scaled down to 50 cells, 30 cells, 10 cells, 5 cells, 2 cells and finally 1 cell. By optimizing multiple steps in the procedure, including direct lysis of cells without performing RNA isolation, we developed LCM-seq that couples LCM with Smart-seq2 for robust and efficient polyA-based RNA sequencing. We applied LCM-seq to mouse and human neuron samples, and demonstrated that LCM-seq can allow us to acquire high quality RNA-seq data from mouse and human tissues to conduct various transcriptomic studies. Developing new sequencing technology LCM-seq to efficiently sequence mouse and human tissues

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Project description:While colorectal cancer liver metastasis (CRCLM) is major cause of death of colorectal cancer, the mechanism of intrahepatic dissemination (trans-lymphatic metastasis) is not fully elucidated. Lymphangiogenesis can be the mechanism of the dissemination, but there are few evidences to prove it. In this study, we attempted to clarify the mechanism using syngeneic murine CRCLM model, especially focusing on vascular endothelial growth factor C (VEGFC), a promoter of lymphangiogenesis. We confirmed that 1) intrahepatic metastasis of CRCLM via lymphatic vessels was seen and lymphangiogenesis was upregulated in the CRCLM-bearing liver, 2) the degree of lymphangiogenesis and CRCLM was significantly correlated with the expression of VEGFC in colorectal cancer (CRC) cells and 3) macrophage inflammatory protein-1α (MIP-1α) was released from CRC cells under the stimulation of VEGFC and induced migration of immature bone marrow derived cells into the liver and differentiation into macrophage, which promoted dissemination of CRCLM. These findings suggest the possibility of therapeutic strategy targeting VEGFC / MIP-1α for diminishing CRCLM. In conclusion, VEGFC in CRC cells promoted trans-lymphatic metastasis of CRCLM by upregulation of lymphangiogenesis directly and indirectly via induction of macrophages derived from bone marrow cells.

2018-09-30 | GSE113235 | GEO

Laser-capture microscopy coupled with Smart-seq2 (LCM-seq) for robust and efficient transcriptomic profiling of mouse and human tissues

2016-07-05 | GSE76514 | GEO

Molecular profiling of lymphatic endothelial cells activation in vitro

Project description:The lymphatic vascular system plays a key role in cancer progression. Indeed, the activation of lymphatic endothelial cells (LECs) through the lymphangiogenic process allows the formation of new lymphatic vessels (LVs) that represent the major route for dissemination of solid tumors. This process is governed by a plethora of cancer-derived and microevironmental mediators that strictly activate and control specific molecular pathways in LECs. In this work we used an in vitro model of LEC activation to trigger lymphangiogenesis using a mix of recombinant pro-lymphangiogenic factors (VFS) and a co-culture system with human melanoma cells. Both systems efficiently activated LECs, and under these experimental conditions RNA sequencing was exploited to unveil the transcriptional profile of activated LECs. Our data demonstrate that both recombinant and tumor cell-mediated activation trigger significant molecular pathways associated with endothelial activation, morphogenesis and cytokine-mediated signaling. In addition, this system provides information on new genes to be further investigated in the lymphangiogenesis process and open the possibility for further exploitation in other tumor contexts where lymphatic dissemination plays a relevant role.

2023-12-13 | GSE247178 | GEO

Meningeal lymphatic vasculature mediates cervical lymph node metastasis of brain tumors through VEGF-C/VEGFR3/eNOS signaling pathway

Project description:Purpose: The rediscovery of meningeal lymphatic vessels (MLVs) suggests a potential linkage between brain tumors and cervical lymph nodes (LNs). In this study, we investigated whether and how meningeal lymphatics regulate the metastasis of brain tumor cells. Experimental Design: We first examined the pattern of MLVs and LNs after tumor cells were injected into the cisterna magna (i.c.m.) or subdural space of mice. The meninges were isolated and analyzed by whole-mount immunofluorescence staining. LN metastasis was analyzed by detecting GFP+ tumor cells. Then we used inducible knock-out mice and AAV-VEGF-C delivery system to study the function of MLVs in mediating the metastasis of brain tumor cells. Finally, RNA-seq was used to determine the expression profiles of meningeal lymphatic endothelial cells (mLECs) in mice with or without tumors. The roles of the endothelial nitric oxide synthetase (eNOS) were evaluated both genetically and pharmacologically in vivo. Results: Meningeal lymphangiogenesis induced by GL261 and B16 tumors was correlated with dCLN swelling and metastasis. dCLN metastasis was suppressed in MLV-defective mice, while promoted in AAV-VEGF-C-treated mice. In addition, we found that VEGF-C/VEGFR3 signaling regulated both meningeal and tumor lymphangiogenesis. Tumor-associated mLECs have a distinct transcriptomic signature, which highly express eNOS. Furthermore, genetic or pharmacological inhibition of eNOS significantly suppressed meningeal lymphangiogenesis and dCLN metastasis. Conclusions: The meningeal lymphatic vasculature mediates the metastasis of brain tumors to cervical LNs, mainly through a VEGF-C/VEGFR3-eNOS signaling pathway, suggesting that MLV may be a potential therapeutic target for the extracranial metastasis of brain tumors.

2020-03-16 | GSE128207 | GEO

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Project description:Herein, we report viral interferon regulatory factor 3 (vIRF3) as a pro-angiogenic factor together with HDAC5 that coordinates with LEC transcriptome, thus resulting in hyper-sprouting formation and ultimately leading to abnormal lymphangiogenesis. Overexpression of vIRF3 in LECs but not blood endothelial cells (BECs) exhibited a unique KSHV-associated angiogenic effect, evidenced by elongated spindle shape, sprouting, and tube formation. Furthermore, using vIRF3 knockout recombinant KSHV, we confirmed that vIRF3 is a critical factor of KSHV-mediated lymphangiogenesis in primary LECs.

2017-12-19 | GSE102132 | GEO

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Project description:Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type-specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs, but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk between iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.

2023-01-16 | GSE201916 | GEO

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