Mesenchymal cancer cell-stromal crosstalk promotes niche activation, epithelial reversion and metastatic colonization
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE63558 | GEO | 2015/11/21
SECONDARY ACCESSION(S): PRJNA268205
REPOSITORIES: GEO
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Project description:The experiment was design to address the intrinsic differences between metastatic cancer stem cells in the primary tumour and during metastatic colonization in the mouse mammary gland tumour model MMTV-pyMT. Total RNA was prepared from the indicated cancer cells freshly isolated, stained and FACS sorted either from primary tumours or from lungs upon intravenous injection of cancer cells.
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Project description:During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization.
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Project description:Loss of E2F transcription factos alters metastatic capacity of MMTV-PyMT tumors. We used microarrays to futher characterize the effects of E2F loss on mammary tumorigenesis in MMTV-PyMT mice.
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Project description:Less than 8% of patients diagnosed with pancreatic ductal adenocarcinomas (PDAC) survive more than five years in part due to late stage diagnosis. Approximately half of PDAC patients exhibit loss of SMAD4, which correlates with increased metastatic disease. Here we demonstrate that SMAD4 is a suppressor of metastatic colonization. Using isogenic human PDAC cell lines expressing or lacking SMAD4, both in vitro and in vivo, we define SMAD4-dependent gene expression changes in metastatic lesions. We performed a pooled in vivo open reading frame (ORF) screen of SMAD4 transcriptional targets and identified genes that, induce tumor seeding and growth at secondary sites. We found that expression of the transcription factor FOSL1 was sufficient to drive metastatic colonization. SMAD4 directly binds and represses the activity of the FOSL1 enhancer. These studies demonstrate a direct role for SMAD4 in regulating metastatic colonization and identify FOSL1 as a SMAD4-regulated gene involved in PDAC progression.
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Project description:SSeCKS/Gravin/AKAP12 (SSeCKS) controls metastasis-associated PKC and Src signaling through direct scaffolding activity. SSeCKS is downregulated in the metastases of many human cancer types, and its forced re-expression suppresses the metastatic behavior of prostate cancer cells. SSeCKS is also downregulated in breast and prostate cancer stroma, and SSeCKS-null mice (KO) are metastasis-prone, suggesting a role in suppressing formation of the pre-metastatic niche. Here, we show that lung colonization and metastasis formation by B16F10 and SM1WT1[Braf V600E] mouse melanoma cells is 9-fold higher in syngeneic KO compared to WT hosts, although there is no difference in orthotopic tumor volumes. Although melanoma cells adhered equally to KO or WT lung fibroblasts (LF), co-injection of melanoma cells with KO (vs. WT) LF increased lung macrometastasis formation in WT hosts, marked by increased melanoma colonization at foci of leaky vasculature. Increased melanoma adhesion on KO lung endothelial cells (LEC) was facilitated by increased E-Selectin levels and by increased STAT3-regulated secretion of senescence-associated factors from KO-LF, such as Vegf. Finally, the ability of SSeCKS to attenuate IFN?-induced Stat3 activation in KO-LF required its Src-scaffolding domain. Taken together, these data suggest that SSeCKS normally suppresses metastatic colonization in the lung by attenuating the expression of Selectin adhesion proteins, which can be controlled autonomously by local endothelial cells or enhanced by senescence factors secreted by neighboring fibroblasts in a SSeCKS-regulated, Src/Stat3-dependent manner.
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Project description:Metastasis is the primary cause of cancer-related mortality and the mechanistically least well understood step of the tumor progression cascade. Employing surgical preclinical metastasis models, we show here that small primary tumors reprogram the body’s vascular endothelium to alter systemic homeostasis and to condition the premetastatic niche for metastatic colonization. Endothelial cells thereby serve as an amplifier of tumor-induced instructive signals. The combined endothelial transcriptomic and serum proteomic screen identified the TGFß pathway signaling specifier LRG1 as an early vascular niche instructor of metastatic colonization. Adjuvant LRG1 inhibition to primary tumor-resected mice delayed metastatic growth and increased overall survival. The study has thereby established the premetastatic systems map of primary tumor-induced vascular changes and identified LRG1 as a therapeutic target for metastasis
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Project description:Monocytes from peripheral blood of tumour-bearing (B6Tg(MMTV-PyMT)634Mul/Lellj) or non-tumor-bearing C57BL/6JCrl mice were FACS sorted and single cells analysed by SMARTseq2
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Project description:Monocytes from peripheral blood of tumour-bearing (B6Tg(MMTV-PyMT)634Mul/Lellj) or non-tumor-bearing C57BL/6JCrl mice were FACS sorted and single cells analysed by SMARTseq2
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Project description:Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression. Experimental design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibitionintermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Conclusions: Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.
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