Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA273661 | ENA |
REPOSITORIES: ENA
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Project description:Cancer-associated fibroblasts (CAF) are crucial in regulating cancer progression, yet the molecular mechanisms that determine the tumor-regulating function of CAF are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that controls the regulatory role of CAF in melanoma growth, invasion and metastasis, and can be manipulated to reprogram and convert CAF to act as tumor suppressors. The Notch1-determined tumor-regulating function is in part mediated by Wnt-induced secreted protein 1 (WISP1). These findings reveal the Notch1âWISP1 axis as a crucial molecular determinant in governing stromal regulation of tumor progression, and establish this axis as a potential therapeutic target Total RNA obtained from MSCD-SF transduced with Cre-GFP/lentivirus in vitro compared to MSCD-SF transduced with GFP/lentivirus. Samples are duplicates.
2016-05-29 | E-GEOD-65316 | biostudies-arrayexpress
Project description:Cancer-associated fibroblasts (CAF) are crucial in regulating cancer progression, yet the molecular mechanisms that determine the tumor-regulating function of CAF are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that controls the regulatory role of CAF in melanoma growth, invasion and metastasis, and can be manipulated to reprogram and convert CAF to act as tumor suppressors. The Notch1-determined tumor-regulating function is in part mediated by Wnt-induced secreted protein 1 (WISP1). These findings reveal the Notch1—WISP1 axis as a crucial molecular determinant in governing stromal regulation of tumor progression, and establish this axis as a potential therapeutic target
2016-05-29 | GSE65316 | GEO
Project description:The signaling events triggered by soluble mediators released from both transformed and stromal cells shape the phenotype of tumoral cells and have significant implications in cancer development and progression. In this study we performed an in vitro heterotypic signaling assay by evaluating the proteome diversity of human dermal fibroblasts after stimulation with the conditioned media obtained from malignant melanoma cells. In addition, we also evaluated the changes in the proteome of melanoma cells after stimulation with their own conditioned media as well as with the conditioned medium from melanoma-stimulated fibroblasts. Our results pointed out to a significant rearrangement in the proteome of stromal and malignant cells upon crosstalk of soluble mediators. The main proteome signature of stimulated cells was related to protein synthesis, which may indicate that this process might be an early response of stimulated stromal cells. In addition, the conditioned medium derived from ‘primed’ stromal cells (melanoma-stimulated fibroblasts) was more effective in altering the functional phenotype (cell migration) of malignant cells than the fibroblast conditioned medium alone. Collectively, self- and cross-stimulation may play a key role in shaping the tumor microenvironment and, more importantly, enable tumoral cells to succeed in the process of melanoma progression and metastasis. Although the proteome landscape of cells participating in such a heterotypic signaling represents a snapshot of a highly dynamic state, understanding the diversity of proteins and enriched biological pathways resulting from stimulated cell states may allow for targeting specific cell regulatory motifs involved in melanoma progression and metastasis.
2020-08-31 | PXD020426 | Pride
Project description:Cancer associated fibroblasts (CAFs) represent a key component of the tumor microenvironment. Possible genomic alterations in these cells remain a point of contention. The skin is constantly exposed to clastogenic insults, such as UVA light that can target directly the stromal compartment, therefore representing a relevant model to study. Here we report that CAFs from skin Squamous Cell Carcinoma (SCC) lesions display chromosomal alterations, with heterogeneous levels of NOTCH1 gene amplification that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 gene amplification is expanded by chronic UVA exposure, which induces a DNA damage response (DDR) to which CAFs are resistant. The selective advantage conferred by NOTCH1 gene amplification and over-expression can be explained by NOTCH1 ability to block DDR-mediated growth arrest through competitive suppression of ATM-FOXO3a association and downstream signaling cascade. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer / stromal cells expansion. Thus, NOTCH1 amplification and increased expression contribute to CAFs evolution and are an attractive target for preventing cancer / stromal cell expansion.
2020-08-25 | GSE113577 | GEO
Project description:In previous investigations, we detected that growth of melanoma cells in mice depleted for adam9 is enhanced. This resulted from molecular alterations in stromal cells cross-communicating to tumor cells and from constitutively altered expression of some molecules, e.g., TIMP1 in stromal fibroblasts lacking adam9. We used microarray analysis to identify the gene expression alterations occurring in stromal cells upon adam9 deletion which lead to the molecular alterations observed and contribute to the tumor phenotype. Primary fibroblasts from adam9 KO and WT mice were cultured in standard conditions to address constitutive gene alterations.
2014-03-28 | E-GEOD-56304 | biostudies-arrayexpress
Project description:PTEN imparts tumor suppression in mice by cell autonomous and non-autonomous mechanisms. Whether these two tumor suppressor mechanisms are mediated through similar or distinct signaling pathways is not known. Here we generated and analyzed knockin mice that express a series of human cancer-derived mutant alleles of PTEN that differentially alter the Akt axis in either stromal or tumor cell compartments of mammary glands. We find that cell non-autonomous tumor suppression by Pten in stromal fibroblasts strictly requires activation of P-Akt signaling, whereas cell autonomous tumor suppression in epithelial tumor cells is independent of overt canonical pathway activation. These findings expose distinct Akt-dependent and independent tumor suppressor functions of PTEN in stromal fibroblasts and tumor cells, respectively, that can be used to guide clinical care of breast cancer patients Wild type, Pten null and PtenF341V primary mouse embryonic fibroblasts isolated from 13.5 day old embryos (E13.5) were cultured, RNA was extracted and Affymetrix gene expression arrays were performed.
2014-12-19 | E-GEOD-64302 | biostudies-arrayexpress
Project description:Tumor-associated stromal cells can enable cancer cells to become insensitive to therapy. They can promote aggressive phenotype in cancer cells, which become less responsive to drugs such as BRAF inhibitors (BRAFi) used to treat melanomas. To clarify potential mechanism behind stromal influence on melanoma, we analyzed gene expression in Melmet 5 melanoma cells grown as mono-cultures or co-cultures with lung fibroblasts with/without BRAFi. We have shown that Melmet 5 growing as co-cultures gained a de-differentiated, invasive transcriptional state, which is known to be linked to BRAFi-resistance. The transcriptional changes induced by BRAFi were much larger in Melmet 5 mono-cultures compared to co-cultures, indicating a much dampened transcriptional response to BRAFi in melanoma under the influence of fibroblasts. We conclude that interaction with the stromal cells stimulate melanoma cell transition to the invasive de-differentiated phenotype, leading to a worse response to BRAF inhibitors. Total RNA was isolated from Melmet 5 cell line growing as mono- or co-cultures with fibroblasts for 72 hours and treated with BRAFi for the last 24 hours.
2015-08-01 | E-GEOD-67637 | biostudies-arrayexpress
Project description:The imbalance of cellular homeostasis during oncogenesis together with the high heterogeneity of tumor-associated stromal cells have a marked effect on the repertoire of the proteins secreted by malignant cells (the secretome). Hence, the study of tumoral secretomes provides insights for understanding the cross-talk between cells within the tumor microenvironment as well as the key effectors for the establishment of the pre-metastatic niche in distant tumor sites. In this context, we performed a proteomic analysis of the secretomes derived from four cell lines: (i) a paired set of fibroblasts - Hs 895. T, a cell line obtained from a lung node metastatic site from a patient who had melanoma and Hs 895.Sk, a skin fibroblast cell line (derived from the same patient); (ii) two malignant metastatic melanoma cell lines - A375, a malignant melanoma cell line from primary source and SH-4, a cell line derived from pleural effusion of a patient with metastatic melanoma. Clustering of expression profiles together with functional enrichment revealed patterns that mirrored each cell type (skin fibroblasts, cancer-associated fibroblasts and metastatic cells). These patterns might be the result of cell-specific protein expression programs and may serve as basis for further proteomic analysis of melanoma cell lines secretomes.
2018-01-02 | PXD007265 | Pride
Project description:Reciprocal interactions between breast cancer cells and the tumor microenvironment are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAFs) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the tumor microenvironment and restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the tumor microenvironment and enhance therapeutic efficacy.
2020-01-01 | GSE136655 | GEO
Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.
2016-04-19 | PXD003223 | Pride