Profiling of freshly isolated mouse lung cancer LLC- and mouse breast cancer 4T1- derived leptomeningeal metastatic cancer cells from different anatomical locations
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE278626 | GEO | 2024/10/13
REPOSITORIES: GEO
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Project description:Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC- and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with 9-cis RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro. In vivo, whereas knockout of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby locally-generated developmental cues metabolically reprogram metastatic cancer cells and suggest novel therapeutic approaches.
2024-10-13 | GSE277504 | GEO
Project description:Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC- and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with 9-cis RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro. In vivo, whereas knockout of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby locally-generated developmental cues metabolically reprogram metastatic cancer cells and suggest novel therapeutic approaches.
2024-10-13 | GSE278624 | GEO
Project description:Profiling of freshly isolated mouse lung cancer LLC- and mouse breast cancer 4T1- derived leptomeningeal metastatic cancer cells from different anatomical locations
| PRJNA1168107 | ENA
Project description:Transcriptomic profiling of freshly isolated mouse lung cancer LLC- and mouse breast cancer 4T1- derived leptomeningeal metastatic cancer cells from different anatomical locations [RNA-Seq]
| PRJNA1162534 | ENA
Project description:Chromatin accessibility profiling of freshly isolated mouse lung cancer LLC- and breast cancer 4T1- derived leptomeningeal metastatic cancer cells from different anatomical locations [ATAC-Seq]
| PRJNA1168110 | ENA
Project description:Breast cancer is one of the major causes of cancer‑related mortality among women worldwide. It metastasizes to distant organs, particularly to bone tissue. Nitrogen‑containing bisphosphonates are mainly used as an adjuvant therapy to inhibit skeletal‑related events; however, there is increasing evidence to suggest that these compounds also exert antitumor effects. In previous studies, the authors synthesized two novel aminomethylidenebisphosphonates (BPs), namely benzene‑1,4‑bis[aminomethylidene(bisphosphonic)] acid (WG12399C) and naphthalene‑1,5‑bis[aminomethylidene(bisphosphonic)] acid (WG12592A). Both BPs exhibited notable antiresorptive activity in a mouse model of osteoporosis. The present study aimed to assess the in vivo anticancer activity of WG12399C and WG12592A in 4T1 breast adenocarcinoma model. WG12399C exerted an anti‑metastatic effect by reducing the number of spontaneous lung metastases by ~66% in comparison to the control. In the experimental metastasis model of 4T1‑luc2‑tdTomato cells, this compound reduced the incidence of tumor metastases in the lungs by approximately half in comparison to the control. Both WG12399C and WG12595A also significantly reduced the size and/or number of bone metastatic foci. Their pro‑apoptotic and anti‑proliferative activity may, at least in part, explain the observed effects. Incubation with WG12399C induced an almost 6‑fold increase in caspase‑3 activity in 4T1 cells. Moreover, cells treated with WG12399C or WG12595A exhibited a 2‑fold reduction in invasiveness through Matrigel. Furthermore, both the BPs were able to sensitize the 4T1 cells to cytostatics. In summary, the results of the present study indicate that the examined aminomethylidene‑BPs may be of particular interest in the context of combined treatment in breast cancer therapy.
| S-EPMC10251367 | biostudies-literature
Project description:Abundance and accessibility render skin-derived stem cells an attractive cell source for tissue engineering applications. Toward assessing their utility, the variability of constructs engineered from human dermis-isolated adult stem (hDIAS) cells was examined with respect to different anatomical locations (foreskin, breast, and abdominal skin), both in vitro and in a subcutaneous, athymic mouse model. All anatomical locations yielded hDIAS cells with multi-lineage differentiation potentials, though adipogenesis was not seen for foreskin-derived hDIAS cells. Using engineered cartilage as a model, tissue engineered constructs from hDIAS cells were compared. Construct morphology differed by location. The mechanical properties of human foreskin- and abdominal skin-derived constructs were similar at implantation, remaining comparable after 4 additional weeks of culture in vivo. Breast skin-derived constructs were not mechanically testable. For all groups, no signs of abnormality were observed in the host. Addition of aggregate redifferentiation culture prior to construct formation improved chondrogenic differentiation of foreskin-derived hDIAS cells, as evident by increases in glycosaminoglycan and collagen contents. More robust Alcian blue staining and homogeneous cell populations were also observed compared to controls. Human DIAS cells elicited no adverse host responses, reacted positively to chondrogenic regimens, and possessed multi-lineage differentiation potential with the caveat that efficacy may differ by anatomical origin of the skin. Taken together, these results suggest that hDIAS cells hold promise as a potential cell source for a number of tissue engineering applications.
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Project description:Cancer nano-therapy has been progressing rapidly with the introduction of many novel drug delivery systems. The previous study has reported on the in vitro cytotoxicity of citral-loaded nanostructured lipid carrier (NLC-Citral) on MDA-MB-231 cells and some preliminary in vivo antitumor effects on 4T1 breast cancer cells challenged mice. However, the in vivo apoptosis induction and anti-metastatic effects of NLC-Citral have yet to be reported. In this study, the in vitro cytotoxic, anti-migration, and anti-invasion effects of NLC-Citral were tested on 4T1 breast cancer cells. In addition, the in vivo antitumor effects of oral delivery of NLC-Citral was also evaluated on BALB/c mice induced with 4T1 cells. In vitro cytotoxicity results showed that NLC-Citral and citral gave similar IC50 values on 4T1 cells. However, wound healing, migration, and invasion assays reflected better in vitro anti-metastasis potential for NLC-Citral than citral alone. Results from the in vivo study indicated that both NLC-Citral and citral have anti-tumor and anti-metastasis effects, whereby the NLC-Citral showed better efficacy than citral in all experiments. Also, the delay of tumor progression was through the suppression of the c-myc gene expression and induction of apoptosis in the tumor. In addition, the inhibition of metastasis of 4T1 cells to lung and bone marrow by the NLC-Citral and citral treatments was correlated with the downregulation of metastasis-related genes expression including MMP-9, ICAM, iNOS, and NF-kB and the angiogenesis-related proteins including G-CSF alpha, Eotaxin, bFGF, VEGF, IL-1alpha, and M-CSF in the tumor. Moreover, NLC-Citral showed greater downregulation of MMP-9, iNOS, ICAM, Eotaxin, bFGF, VEGF, and M-CSF than citral treatment in the 4T1-challenged mice, which may contribute to the better anti-metastatic effect of the encapsulated citral. This study suggests that NLC is a potential and effective delivery system for citral to target triple-negative breast cancer.
| S-EPMC7321383 | biostudies-literature
Project description:The mammary luminal cell compartment is heterogeneous. In adult virgin mice, it contains clonogenic luminal progenitors and non-clonogenic luminal cells expressing estrogen and progesterone receptors that can be discrimated by their cell surface expression of ICAM-1. We have separated ICAM1+ luminal progenitors and ICAM- non-clonogenic luminal cells and analyzed their transcriptomic profiles. After showing that the luminal progenitor population overexpressed Met, Trp53 and numerous p53 target genes, we analyzed how the p53 and Met signaling pathways cooperate to control the function and plasticity of luminal progenitors.
2019-02-05 | GSE122928 | GEO
Project description:BackgroundLeptomeningeal metastasis (LM), or spread of cancer cells into the cerebrospinal fluid (CSF), is characterized by a rapid onset of debilitating neurological symptoms and markedly bleak prognosis. The lack of reproducible in vitro and in vivo models has prevented the development of novel, LM-specific therapies. Although LM allows for longitudinal sampling of floating cancer cells with a spinal tap, attempts to culture patient-derived leptomeningeal cancer cells have not been successful.AimWe, therefore, employ leptomeningeal derivatives of human breast and lung cancer cell lines that reproduce both floating and adherent phenotypes of human LM in vivo and in vitro.Methods and resultsWe introduce a trypsin/EDTA-based fractionation method to reliably separate the two cell subsets and demonstrate that in vitro cultured floating cells have decreased proliferation rate, lower ATP content, and are enriched in distinct metabolic signatures. Long-term fractionation and transcriptomic analysis suggest high degree plasticity between the two phenotypes in vitro. Floating cells colonize mouse leptomeninges more rapidly and associate with shortened survival. In addition, patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI positive) disease.ConclusionTogether, these data support mechanistic evidence of a metabolic adaptation that allows cancer cells to thrive in their natural environment but leads to death in vitro.
| S-EPMC7772527 | biostudies-literature