PTEN restrains tumor expansion through cell autonomous and non-autonomous mechanisms
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ABSTRACT:
PROVIDER: PRJNA1256273 | ENA |
REPOSITORIES: ENA
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Project description:To gain insight into transcriptional changes that occur in SmoM2 SHH-MB tumor cells that lack Pten and could account for the cell autonomous changes we observed in tumors of a mouse model, we performed single cell RNA-sequencing (scRNA-seq) of whole tumors dissected from P22 SmoM2 (Atoh1-FlpoER/+; R26MASTR/LSL-SmoM2) and P16 SmoM2-Ptenfl/fl (Atoh1-FlpoER/+; R26MASTR/LSL-SmoM2; Ptenfl/fl) mice (n = 2 per genotype).
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Project description:PTEN imparts tumor suppression in mice by cell autonomous and non-autonomous mechanisms. Whether these two tumor suppressor roles 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 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. PtenF341V, PtenWT/null, and Pten null CDH1 positive epithelials cells of mammary ducts from 8 week old female mice were isolated by FACS, RNA was extracted and Affymetrix gene expression arrays were performed.
2014-12-19 | E-GEOD-64303 | biostudies-arrayexpress
Project description:PTEN imparts tumor suppression in mice by cell autonomous and non-autonomous mechanisms. Whether these two tumor suppressor roles 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 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
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Project description:Chronic inflammation is known to associate with prostate cancer development, but how epithelium-associated cancer initiating events cross-talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) occurring intra-prostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1+CD11b+ cells, but not those isolated from the spleen of the same tumor bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf-1 and IL-1β, two genes known to induce MDSC expansion and immunosuppressive activities. Treating Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression. Laser-capture microdissection was used to extract epithelial cells from murine benign and Pten null prostate tumors. Their transcript levels were measured by the custom Agilent 4x44K whole mouse genome expression oligonucleotide microarrays. Each cohort had three biological replicates.
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Project description:Chronic inflammation is known to associate with prostate cancer development, but how epithelium-associated cancer initiating events cross-talk to inflammatory cells during prostate cancer initiation and progression is largely unknown. Using the Pten null murine prostate cancer model, we show an expansion of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) occurring intra-prostatically immediately following epithelium-specific Pten deletion without expansion in hematopoietic tissues. This MDSC expansion is accompanied by sustained immune suppression. Prostatic Gr-1+CD11b+ cells, but not those isolated from the spleen of the same tumor bearing mice, suppress T cell proliferation and express high levels of Arginase 1 and iNOS. Mechanistically, loss of PTEN in the epithelium leads to a significant upregulation of genes within the inflammatory response and cytokine-cytokine receptor interaction pathways, including Csf-1 and IL-1β, two genes known to induce MDSC expansion and immunosuppressive activities. Treating Pten null mice with the selective CSF-1 receptor inhibitor GW2580 decreases MDSC infiltration and relieves the associated immunosuppressive phenotype. Our study indicates that epithelium-associated tumor initiating events trigger the secretion of inflammatory cytokines and promote localized MDSC expansion and immune suppression, thereby promoting tumor progression Custom Agilent 4x44K whole mouse genome expression oligonucleotide microarrays were used to measure transcript levels in murine Pten null prostate cancer cell lines. Benign mouse prostate epithelia as wild type control against cell lines. Each cohort had three biological replicates.
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Project description:Hematopoietic stem cells (HSC) rapidly expand during fetal development and after stress. Here, we identify BCLAF1 as a regulator of HSC repopulation activity with functions in propagation of fetal HSCs and hematopoietic reconstitution after stem cell transplantation. Using mice with hematopoietic-specific and inducible deletion of Bclaf1, we find that BCLAF1 promotes fetal HSC expansion but is dispensible for maintenance of adult HSCs at steady state. Loss of BCLAF1 in either fetal or adult HSCs significantly impairs their self-renewal and multi-lineage reconstitution activity after stem cell transplantation. Single-cell RNA sequencing of fetal hematopoietic progenitors reveals that loss of BCLAF1 reduces long-term HSCs and restrains expression of stress response genes. BCLAF1 associates with chromatin throughout the genome of fetal and adult hematopoietic cells, likely through indirect mechanisms, to regulate transcriptional programs. These results establish a novel function for the transcriptional regulator BCLAF1 in limiting stress responses in HSCs to preserve their expansion during embryogenesis and after stem cell transplant.
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