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Bi-directional c-Kit–mKitL signalling promotes tumour endothelial cell differentiation and triple-negative breast cancer progression

ABSTRACT: Transcriptomic analysis of lineage traced KitL+ endothelial cells from naive, small and large tumour bearing mammary gland tissue

ORGANISM(S): Mus musculus

PROVIDER: GSE154000 | GEO | 2021/01/31

REPOSITORIES: GEO

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Bi-directional signaling by membrane-bound KitL induces proliferation and co-ordinates thymic endothelial cell and thymocyte expansion

Project description:The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit– and mKitL–expressing NIH3T3 cells results in signaling through mKitL: c-Kit–bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL–c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL–c-Kit signaling for their proliferation.

2018-11-21 | PXD011061 | Pride

Bi-directional c-Kit–mKitL signalling promotes tumour endothelial cell differentiation and triple-negative breast cancer progression

Project description:Bi-directional c-Kit–mKitL signalling promotes tumour endothelial cell differentiation and triple-negative breast cancer progression

| PRJNA644787 | ENA

Wnt signalling is a bi-directional vulnerability of cancer cells.

Project description:Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.

| S-EPMC5312386 | biostudies-literature

c-kit Signaling Inhibits Bone Development by Regulating Skeletal Stem Cell Precursors in Fetal Bone Marrow

Project description:c-kit signaling plays pivotal roles in regulating the self-renewal and/or differentiation of many adult stem cells, such as hematopoietic stem cells. However, it remains controversial whether c-kit is expressed by and contribute to skeletal stem cells (SSCs). To test this, we lineage-traced c-kit+ cells and investigated the physiological importance of c-kit+ cells and c-kit signaling in bone development. We found that c-kit was not expressed by postnatal SSCs, but by fetal SSC precursors at the growth cartilage. Lineage-tracing of fetal c-kit+ cells marked approximately 20% of Lepr+ bone marrow stromal cells, generating nearly half of all osteoblasts in adult bone marrow. Disruption of mTOR signaling in c-kit+ cells impaired bone formation. Conditional deletion of Kitl (c-kit ligand, also known as Scf) from fetal, but not adult bone marrow stromal cells increased bone formation. Together, our work identified c-kit+ SSC precursors as an important source of bones formed during development. The osteogenic differentiation of these cells is temporally inhibited by Kitl from the bone marrow microenvironment.

2020-02-27 | GSE146002 | GEO

Thymic T-cell progenitor development is supported by membrane bound Kit ligand provided by a combined vascular endothelial and epithelial niche.

Project description:Gene expression analysis of purified KitL-tomato+ and KitL-tomato- thymic vascular endothelial cells, cortical and medullary thymic epithelial cells from 5 weeks old male kitL-tomato reporter mice

2016-01-18 | GSE62741 | GEO

Afar triple junction triggered by plume-assisted bi-directional continental break-up.

Project description:Divergent ridge-ridge-ridge (R-R-R) triple junctions are one of the most remarkable, yet largely enigmatic, features of plate tectonics. The juncture of the Arabian, Nubian, and Somalian plates is a type-example of the early development stage of a triple junction where three active rifts meet at a 'triple point' in Central Afar. This structure may result from the impingement of the Afar plume into a non-uniformly stressed continental lithosphere, but this process has never been reproduced by self-consistent plume-lithosphere interaction experiments. Here we use 3D thermo-mechanical numerical models to examine the initiation of plume-induced rift systems under variable far-field stress conditions. Whereas simple linear rift structures are preferred under uni-directional extension, we find that more complex patterns form in response to bi-directional extension, combining one or several R-R-R triple junctions. These triple junctions optimize the geometry of continental break-up by minimizing the amount of dissipative mechanical work required to accommodate multi-directional extension. Our models suggest that Afar-like triple junctions are an end-member mode of plume-induced bi-directional rifting that combines asymmetrical northward pull and symmetrical EW extension at similar rates.

| S-EPMC6170478 | biostudies-literature

Thymic T-cell progenitor development is supported by membrane bound Kit ligand provided by a combined vascular endothelial and epithelial niche.

2016-01-18 | E-GEOD-62741 | biostudies-arrayexpress

Spatial distribution and receptor specificity of zebrafish Kit system--evidence for a Kit-mediated bi-directional communication system in the preovulatory ovarian follicle.

Project description:Consisting of Kit ligand and receptor Kit, the Kit system is involved in regulating many ovarian functions such as follicle activation, granulosa cell proliferation, and oocyte growth and maturation. In mammals, Kit ligand is derived from the granulosa cells and Kit receptor is expressed in the oocyte and theca cells. In the zebrafish, the Kit system contains two ligands (Kitlga and Kitlgb) and two receptors (Kita and Kitb). Interestingly, Kitlga and Kitb are localized in the somatic follicle cells, but Kitlgb and Kita are expressed in the oocyte. Using recombinant zebrafish Kitlga and Kitlgb, we demonstrated that Kitlga preferentially activated Kita whereas Kitlgb specifically activated Kitb by Western analysis for receptor phosphorylation. In support of this, Kitlgb triggered a stronger and longer MAPK phosphorylation in follicle cells than Kitlga, whereas Kitlga but not Kitlgb activated MAPK in the denuded oocytes, in agreement with the distribution of Kita and Kitb in the follicle and their specificity for Kitlga and Kitlgb. Further analysis of the interaction between Kit ligands and receptors by homology modeling showed that Kitlga-Kita and Kitlgb-Kitb both have more stable electrostatic interaction than Kitlgb-Kita or Kitlga-Kitb. A functional study of Kit involvement in final oocyte maturation showed that Kitlga and Kitlgb both suppressed the spontaneous maturation significantly; in contrast, Kitlgb but not Kitlga significantly promoted 17α, 20β-dihydroxy-4-pregnen-3-one (DHP) -induced oocyte maturation. Our results provided strong evidence for a Kit-mediated bi-directional communication system in the zebrafish ovarian follicle, which could be part of the complex interplay between the oocyte and the follicle cells in the development of follicles.

| S-EPMC3568072 | biostudies-literature

Stromal KITL/SCF promotes pancreas tissue homeostasis and restrains tumor progression.

Project description:Components of normal tissue architecture serve as barriers to tumor progression. Inflammatory and wound-healing programs are requisite features of solid tumorigenesis, wherein alterations to immune and non-immune stromal elements enable loss of homeostasis during tumor evolution. The precise mechanisms by which normal stromal cell states limit tissue plasticity and tumorigenesis, and which are lost during tumor progression, remain largely unknown. Here we show that healthy pancreatic mesenchyme expresses the paracrine signaling molecule KITL, also known as stem cell factor, and identify loss of stromal KITL during tumorigenesis as tumor-promoting. Genetic inhibition of mesenchymal KITL in the contexts of homeostasis, injury, and cancer together indicate a role for KITL signaling in maintenance of pancreas tissue architecture, such that loss of the stromal KITL pool increased tumor growth and reduced survival of tumor-bearing mice. Together, these findings implicate loss of mesenchymal KITL as a mechanism for establishing a tumor-permissive microenvironment.

2024-10-14 | GSE278857 | GEO

Bi-directional interactions of omental adipocytes and SKOV3ip1 cells

Project description:Primary human omental adipocytes were isolated from patients with non-cancer conditions. Subsequently, gene expression profiled in adipocytes and ovarian cancer cell line (SKOV3ip1) alone (control) or under co-culture conditions. Following co-culture cells were separated and total RNA isolated for microarray analysis.

2023-07-24 | GSE235641 | GEO

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