Tumor-initiating stem cell shapes its microenvironment into an immunosuppressive barrier and pro-tumorigenic niche
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ABSTRACT:
PROVIDER: PRJNA561771 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10017100.fastq.gz | Fastqsanger.gz | |||
| SRR10017101.fastq.gz | Fastqsanger.gz | |||
| SRR10017102.fastq.gz | Fastqsanger.gz | |||
| SRR10017103.fastq.gz | Fastqsanger.gz | |||
| SRR10017104.fastq.gz | Fastqsanger.gz |
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Project description:Tumor-initiating stem cells (TSCs) are critical for drug resistance and immune escape. However, the mutual regulations between TSC and tumor microenvironment (TME) remain unclear. Using DNA-label retaining, single-cell RNA sequencing (scRNA-seq), and other approaches, we investigated intestinal adenoma in response to chemoradiotherapy (CRT), thus identifying therapy-resistant TSCs (TrTSCs). We find bidirectional crosstalk between TSCs and TME using CellPhoneDB analysis. An intriguing finding is that TSCs shape TME into a landscape that favors TSCs for immunosuppression and propagation. Using adenoma-organoid co-cultures, niche-cell depletion, and lineaging tracing, we characterize a functional role of cyclooxygenase-2 (Cox-2)-dependent signaling, predominantly occurring between tumor-associated monocytes and macrophages (TAMMs) and TrTSCs. We show that TAMMs promote TrTSC proliferation through prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, which enhances β-catenin activity via AKT phosphorylation. Thus, our study shows that the bidirectional crosstalk between TrTSC and TME results in a pro-tumorigenic and immunosuppressive contexture.
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Project description:Tumor-initiating stem cells (TSCs) are critical for drug resistance and immune escape. However, the mutual regulations between TSC and tumor microenvironment (TME) remain unclear. Using DNA-label retaining, single-cell RNA sequencing (scRNA-seq), and other approaches, we investigated intestinal adenoma in response to chemoradiotherapy (CRT), thus identifying therapy-resistant TSCs (TrTSCs). We find bidirectional crosstalk between TSCs and TME using CellPhoneDB analysis. An intriguing finding is that TSCs shape TME into a landscape that favors TSCs for immunosuppression and propagation. Using adenoma-organoid co-cultures, niche-cell depletion, and lineaging tracing, we characterize a functional role of cyclooxygenase-2 (Cox-2)-dependent signaling, predominantly occurring between tumor-associated monocytes and macrophages (TAMMs) and TrTSCs. We show that TAMMs promote TrTSC proliferation through prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, which enhances β-catenin activity via AKT phosphorylation. Thus, our study shows that the bidirectional crosstalk between TrTSC and TME results in a pro-tumorigenic and immunosuppressive contexture.
| S-EPMC8451448 | biostudies-literature
Project description:An increased serum alkaline phosphatase concentration is known to be associated with a negative prognosis in canine and human osteosarcoma. To expand upon previous studies regarding the biological relevance of increased serum alkaline phosphatase as a negative prognostic factor, xenogeneic heterotopic transplants were performed using six canine primary osteosarcoma cell lines generated from patients with differing serum alkaline phosphatase concentrations (3 normal and 3 increased). Three of the six cell lines were capable of generating tumors and tumor formation was independent of the serum alkaline phosphatase status of the cell line. Microarray analysis identified 379 genes as being differentially-expressed between the tumorigenic and non-tumorigenic cell lines. Frizzled-6 was up-regulated to the greatest extent (7.78 fold) in tumorigenic cell lines compared to non-tumorigenic cell lines. Frizzled-6, a co-receptor for Wnt ligands has been associated with enhanced tumor-initiating cells and poor prognosis for other tumors. The increased expression of frizzled-6 was confirmed by QPCR and Western blot analysis. Additionally, the tumorigenic cell lines also had an increase in the percentage of side population cells compared to non-tumorigenic cell lines (5.89% versus 1.58%, respectively). There were no differences in tumorigenicity, frizzled-6, or percentage of side population cells noted between osteosarcoma cell lines generated from patients of differing serum alkaline phosphatase concentration. However, to our knowledge this is the first study to identified frizzled-6 as a possible marker of osteosarcoma cell populations with enhanced tumorigenicity and side population cells. Future work will focus on defining the role of frizzled-6 in osteosarcoma tumorigenesis and tumor-initiating cells. A total of six canine primary osteosarcoma cell lines were used in this study. Three cell lines were capable of forming tumors when transplanted into mice (tumorigenic) and three cell lines were not capable of forming tumors upon transplant into mice (non-tumorigenic). The gene expression data is from the primary cell lines, not the transplanted cells. There were no reference cell lines or controls used in this study.
2014-05-22 | E-GEOD-57884 | biostudies-arrayexpress
Project description:An increased serum alkaline phosphatase concentration is known to be associated with a negative prognosis in canine and human osteosarcoma. To expand upon previous studies regarding the biological relevance of increased serum alkaline phosphatase as a negative prognostic factor, xenogeneic heterotopic transplants were performed using six canine primary osteosarcoma cell lines generated from patients with differing serum alkaline phosphatase concentrations (3 normal and 3 increased). Three of the six cell lines were capable of generating tumors and tumor formation was independent of the serum alkaline phosphatase status of the cell line. Microarray analysis identified 379 genes as being differentially-expressed between the tumorigenic and non-tumorigenic cell lines. Frizzled-6 was up-regulated to the greatest extent (7.78 fold) in tumorigenic cell lines compared to non-tumorigenic cell lines. Frizzled-6, a co-receptor for Wnt ligands has been associated with enhanced tumor-initiating cells and poor prognosis for other tumors. The increased expression of frizzled-6 was confirmed by QPCR and Western blot analysis. Additionally, the tumorigenic cell lines also had an increase in the percentage of side population cells compared to non-tumorigenic cell lines (5.89% versus 1.58%, respectively). There were no differences in tumorigenicity, frizzled-6, or percentage of side population cells noted between osteosarcoma cell lines generated from patients of differing serum alkaline phosphatase concentration. However, to our knowledge this is the first study to identified frizzled-6 as a possible marker of osteosarcoma cell populations with enhanced tumorigenicity and side population cells. Future work will focus on defining the role of frizzled-6 in osteosarcoma tumorigenesis and tumor-initiating cells.
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Project description:Background & aimsA therapeutically challenging subset of cells, termed cancer stem cells (CSCs) are responsible for cholangiocarcinoma (CCA) clinical severity. Presence of tumor-associated macrophages (TAMs) has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may actively shape their tumor-supportive immune niche.MethodsCCA cells were cultured in 3D conditions to generate spheres. CCA sphere analysis of in vivo tumorigenic-engraftment in immune-deficient mice and molecular characterization was performed. The in vitro and in vivo effect of CCA spheres on macrophage precursors was tested after culturing healthy donor cluster of differentiation (CD)14+ with CCA-sphere conditioned medium.ResultsCCA spheres engrafted in 100% of transplanted mice and revealed a significant 20.3-fold increase in tumor-initiating fraction (p=0.0011) and a sustained tumorigenic potential through diverse xenograft-generations. Moreover, CCA spheres were highly enriched for CSC, liver cancer and embryonic stem cell markers both at gene and protein levels. Next, fluorescence-activated cell sorting analysis showed that in the presence of CCA sphere conditioned medium, CD14+ macrophages expressed key markers (CD68, CD115, human leukocyte antigen-D related, CD206) indicating that CCA sphere conditioned medium was a strong macrophage-activator. Gene expression profile of CCA sphere activated macrophages revealed unique molecular TAM-like features confirmed by high invasion capacity. Also, freshly isolated macrophages from CCA resections recapitulated a similar molecular phenotype of in vitro-educated macrophages. Consistent with invasive features, the largest CD163+ set was found in the tumor front of human CCA specimens (n=23) and correlated with a high level of serum cancer antigen 19.9 (n=17). Among mediators released by CCA spheres, only interleukin (IL)13, IL34 and osteoactivin were detected and further confirmed in CCA patient sera (n=12). Surprisingly, a significant association of IL13, IL34 and osteoactivin with sphere stem-like genes was provided by a CCA database (n=104). In vitro combination of IL13, IL34, osteoactivin was responsible for macrophage-differentiation and invasion, as well as for in vivo tumor-promoting effect.ConclusionCCA-CSCs molded a specific subset of stem-like associated macrophages thus providing a rationale for a synergistic therapeutic strategy for CCA-disease.Lay summaryImmune plasticity represents an important hallmark of tumor outcome. Since cancer stem cells are able to manipulate stromal cells to their needs, a better definition of the key dysregulated immune subtypes responsible for cooperating in supporting tumor initiation may facilitate the development of new therapeutic approaches. Considering that human cholangiocarcinoma represents a clinical emergency, it is essential to move to predictive models in order to understand the adaptive process of macrophage component (imprinting, polarization and maintenance) engaged by tumor stem-like compartment.
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