Gene expression profile of tumor-associated macrophages in human colorectal liver metastasis (CLM)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE131353 | GEO | 2020/08/05
REPOSITORIES: GEO
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Project description:Colorectal cancer is a major cause of mortality worldwide. Most patients develop colorectal liver metastases (CLM), and for such patients hepatectomy combined with chemotherapy may be curative. Nevertheless, in the era of precision medicine there is a critical need of prognostic markers to cope with the heterogeneity of CLM patients. Tumor-associated macrophages (TAMs) pave the way to tissue invasion and intravasation providing a nurturing microenvironment formetastases. The quantification of immune landscape of tumors has provided novel prognostic indicators of cancer progression, and the quantification of TAMs might explain the heterogeneity of CLM patients. Here, we will investigate the development of a new diagnostic tool based on TAMs with the aim to define the causative role of TAMs in CLM patients. This will open new clinical scenarios both for the diagnosis, therapy and prognosis, leading to the refinement of the therapeutic output in a personalized medicine perspective.
| 2300850 | ecrin-mdr-crc
Project description:More than 50% of all patients with colorectal cancer (CRC) develop liver metastasis (CLM) that are characterized by poor prognosis and lack of reliable prognostic markers. Vd1 T cells are gd T innate-like lymphocytes endowed with a broad array of antitumor functions at peripheral tissues, but little is known about their impact in the pathophysiology of CLM. We assessed the phenotype and functions by flow cytometry, clonotype by gdTCR-sequencing, transcriptional profiles by single cell RNA-sequencing and clinical impact of human Vd1 T cells isolated from peripheral blood (PB), tumor-free liver parenchyma surrounding CLM (TFLP) and metastatic tumor (MT) from a large cohort of CLM patients. We show here that CLM tissue is highly enriched of CD69+ Vd1 T effector (TEF) cells in the TFLP area. These cells have a peculiar phenotype, high anti-tumour potential and correlate with a better clinical outcome in terms of lower numbers of liver metastatic lesions and longer overall survival (OS). Moreover, the specific terminally differentiated (TEMRA) CD69+ Vd1 cells can egress CLM tissue to re-circulate in the bloodstream, where they retains high effector functions and show phenotypic/transcriptional and gdTCR profiles that resemble their liver origin. Importantly, high frequencies of CD69+TEMRA Vd1 cells in PB predict a longer OS of CLM patients that is not affected by the neo-adjuvant chemotherapy/immunotherapy regimens administered to CLM patients. The presence at high frequencies of liver memory CD69+TEMRA Vd1 cells in CLM homing to PB represents a new important target to better predict CLM clinical outcomes and to develop novel protocols of adoptive cell transfer therapies.
2023-10-03 | GSE159051 | GEO
Project description:Macrophages (Mf) are the most abundant mononuclear phagocytes in tumor tissues and hold promise as therapeutic targets and indicators of disease progression. In this work, we mapped by single-cell analysis the distinct Mf populations infiltrating the invasive margin and normal adjacent regions of human colo-rectal liver metastasis (CLM), and we exploited this information to identify non redundant markers with clinical relevance. Different populations were enriched in the invasive margin, including early-mature, inflammatory Mf (MoMf) expressing the monocytic markers S100A12 and SERPINB2, and a more mature population (TAMs) expressing CD68, GPNMB and TREM2. TAMs were enriched in pathways of matrix degradation, angiogenesis and lipid metabolism, similarly to dysfunctional macrophages described in other tumors. Cell-cell interaction analysis with CD8+ T cells defined opposing roles of MoMf, predicted to interact via IL-15, and TAMs, engaging T cells via IL-20 and IL-10. By multiplex immunofluorescence in CLM sections, we confirmed that SERPINB2 and GPNMB are expressed by different Mf subsets, with distinct topographical distribution and opposite association with patient clinical outcome.
2024-01-29 | GSE254364 | GEO
Project description:Macrophages (Mf) are the most abundant mononuclear phagocytes in tumor tissues and hold promise as therapeutic targets and indicators of disease progression. In this work, we mapped by single-cell analysis the distinct Mf populations infiltrating the invasive margin and normal adjacent regions of human colo-rectal liver metastasis (CLM), and we exploited this information to identify non redundant markers with clinical relevance. Different populations were enriched in the invasive margin, including early-mature, inflammatory Mf (MoMf) expressing the monocytic markers S100A12 and SERPINB2, and a more mature population (TAMs) expressing CD68, GPNMB and TREM2. TAMs were enriched in pathways of matrix degradation, angiogenesis and lipid metabolism, similarly to dysfunctional macrophages described in other tumors. Cell-cell interaction analysis with CD8+ T cells defined opposing roles of MoMf, predicted to interact via IL-15, and TAMs, engaging T cells via IL-20 and IL-10. By multiplex immunofluorescence in CLM sections, we confirmed that SERPINB2 and GPNMB are expressed by different Mf subsets, with distinct topographical distribution and opposite association with patient clinical outcome.
2023-05-02 | GSE200253 | GEO
Project description:Macrophages (Mf) are the most abundant mononuclear phagocytes in tumor tissues and hold promise as therapeutic targets and indicators of disease progression. In this work, we mapped by single-cell analysis the distinct Mf populations infiltrating the invasive margin and normal adjacent regions of human colo-rectal liver metastasis (CLM), and we exploited this information to identify non redundant markers with clinical relevance. Different populations were enriched in the invasive margin, including early-mature, inflammatory Mf (MoMf) expressing the monocytic markers S100A12 and SERPINB2, and a more mature population (TAMs) expressing CD68, GPNMB and TREM2. TAMs were enriched in pathways of matrix degradation, angiogenesis and lipid metabolism, similarly to dysfunctional macrophages described in other tumors. Cell-cell interaction analysis with CD8+ T cells defined opposing roles of MoMf, predicted to interact via IL-15, and TAMs, engaging T cells via IL-20 and IL-10. By multiplex immunofluorescence in CLM sections, we confirmed that SERPINB2 and GPNMB are expressed by different Mf subsets, with distinct topographical distribution and opposite association with patient clinical outcome.
2023-05-02 | GSE200068 | GEO
Project description:PURPOSE: We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). PATIENTS AND METHODS: We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) of the expressed genes between these two groups. To characterize the clinical relevance of two highly-ranked differentially expressed signature genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.035), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p < 0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p < 0.0001) and LEF1 overexpression (p < 0.05) as important prognostic markers, but not tumor grade or SPP1. CONCLUSION: Among signature genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis. cDNA microarrays from the Stanford Functional Genomics Facility were used to perform mRNA transcript profiling of 31 freshly-frozen primary colorectal cancer specimens, and compared to published profiles of 32 unmatched colorectal liver metastases and 12 normal liver specimens.
2011-03-22 | E-GEOD-22834 | biostudies-arrayexpress
Project description:PURPOSE: We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). PATIENTS AND METHODS: We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) of the expressed genes between these two groups. To characterize the clinical relevance of two highly-ranked differentially expressed signature genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.035), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p < 0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p < 0.0001) and LEF1 overexpression (p < 0.05) as important prognostic markers, but not tumor grade or SPP1. CONCLUSION: Among signature genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
2011-03-22 | GSE22834 | GEO
Project description:Tumor-associated macrophages (TAMs) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor invasive front, participate in integrin recycling, ECM remodeling and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor Yes-Associated Protein. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for cancer patient stratification. DAB2 is therefore central for the pro-metastatic activity of TAMs.
2020-07-13 | GSE152674 | GEO
Project description:Clinical and experimental evidence indicates that tumor-associated macrophages (TAMs) promote malignant progression. In breast cancer, TAMs enhance tumor angiogenesis, tumor cell invasion, matrix remodeling, and immune suppression against the tumor. In this study, we examined late-stage mammary tumors from a transgenic mouse model of breast cancer. We used flow cytometry under conditions that minimized gene expression changes to isolate a rigorously defined TAM population previously shown to be associated with invasive carcinoma cells. The gene expression signature of this population was compared with a similar population derived from spleens of non-tumor-bearing mice using high-density oligonucleotide arrays. Using stringent selection criteria, transcript abundance of 460 genes was shown to be differentially regulated between the two populations. Bioinformatic analyses of known functions of these genes indicated that formerly ascribed TAM functions, including suppression of immune activation and matrix remodeling, as well as multiple mediators of tumor angiogenesis, were elevated in TAMs. Further bioinformatic analyses confirmed that a pure and valid TAM gene expression signature in mouse tumors could be used to assess expression of TAMs in human breast cancer. The data derived from these more physiologically relevant autochthonous tumors compared with previous studies in tumor xenografts suggest tactics by which TAMs may regulate tumor angiogenesis and thus provide a basis for exploring other transcriptional mediators of TAM trophic functions within the tumor microenvironment. Tumor-associated macrophages from late-stage mouse mammary tumors compared to splenic macrophages from non-tumor-bearing littermate controls. 4 biological replicates of each population were compared via gene expression arrays.
2010-06-21 | E-GEOD-18404 | biostudies-arrayexpress
Project description:Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAb) and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift towards an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T-cell proliferation and IFNγ secretion. Indeed, M1-like and M2-like macrophage differentiation involves complex signaling pathways leading to specific gene expression profiles. Typically, stimuli from the TME induce pathways including JAK/STATs, MAPK, PI3K/AKT, NOTCH and NF-κB influencing TAMs polarization. We investigated the signaling pathways activated in monocytes and M-CSF-induced M2-like macrophages upon BTN2A1 engagement using anti-BTN2A mAb5. After 30 min of treatment, we observed phosphorylation of MAPKs (i.e. ERK1/2, P38 and JNK) in CD14+ monocytes and in M2-like macrophages, unlike isotype control-treated cells. In contrast, the PI3K/AKT, JAK/STAT, and NF-kB pathways were not consistently activated after 30 min of anti-BTN2A mAb5 treatment. Since BTN2A1 lacks intrinsic kinase activity, we explored whether BTN2A1 could form complexes with molecular partners in M2-like macrophages that provide kinase activity. We prepared lysates from M2-like macrophages treated with mAb5 or with its isotype control for 30 min and performed immunoprecipitation (IP) using another anti-BTN2A mAb followed by western blotting with anti-phosphoTyrosine (pTyr). A 70 kDa was co-immunoprecipitated with BTN2A1 and revealed by the anti-pTyr in lysates from anti-BTN2A mAb5-treated M2-like macrophages. To identify which Tyrosine kinase is enriched in anti-BTN2A mAb5-treated M2-like macrophages, we performed LC-MS/MS on anti-pTyr immunoprecipitates from treated cells. Several tyrosine kinases, including P38α/δ and JNK, were enriched. Notably, SYK was also identified and matched the 72kDa molecular weight of the pTyr band co-immunoprecipitated with BTN2A1.
2024-09-02 | PXD055262 | Pride