Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE246662 | GEO | 2024/07/29
REPOSITORIES: GEO
Similar Datasets
Project description:We established an in vivo model of organ-specific colorectal cancer metastasis and demonstrated that the CD110+ tumor initiating cells contribute for colorectal liver metastasis. To gain a deeper understanding of its metastatic capacity, we performed a genome-wide transcriptome analysis on the CD110+ tumor cells derived from primary colon xenografts and their matched liver metastases. Results provide important information of the responses of the CD110+ cells during the process of liver colonization. Total RNA obtained from the CD110+ cells sorted from primary colorectal tumors (CRC102-PT and CRC108-PT) compared to those from the corresponding liver metastases (CRC102-LM and CRC108-LM).
2015-01-01 | E-GEOD-64595 | biostudies-arrayexpress
Project description:The liver is one of the most-favored distant metastatic sites for solid tumors, and interactions between cancer cells and components of the hepatic microenvironment are essential for liver metastasis (LM). Although sex is one of the determinants for primary liver cancer, sexual disparity/dimorphism in LM (SDLM) and the underlying mechanisms remain unclear. We herein demonstrated a significant male-biased SDLM, which was attributed to host androgen/androgen receptor (AR) signaling that promoted hepatic seeding of tumor cells and subsequent outgrowth in a neutrophil-dependent manner. Mechanistically, androgen/AR signaling promoted hepatic accumulation of neutrophils by promoting proliferation and development of neutrophil precursors in the bone marrow, as well as modulating hepatic recruitment of neutrophils and their functions. Antagonizing the androgen/AR/neutrophil axis significantly mitigated LM in males. Our data thus reveal an important role of androgen in LM and suggest that androgen/AR modulation represents a promising target for LM therapy in men.
2022-03-12 | GSE198175 | GEO
Project description:Cholestasis, a serious complication of liver metastasis (LM), contributes to dismal prognosis in patients with colorectal cancer and LM. However, the mechanism underlying the effect of cholestasis on the development of LM or pre-metastatic microenvironment in the liver remains elusive. In this study, we discovered that cholestasis accelerated the progression of LM and is associated with increased neutrophil infiltration, T-cell exclusion, and exhaustion. Besides, Tβ-MCA and GCA promoted the expression of Arg1 and iNOS in neutrophils via the p38/MAPK signaling pathway. The significant suppression of the activation and cytotoxic effects of CD8+ T cells during co-culture with BA-pretreated neutrophils indicated that BAs directly induce the polarization of immunosuppressive neutrophils. Importantly, targeting BA anabolism with Obeticholic acid effectively suppressed the LM of colorectal cancer in a cholestasis mouse model. Our findings suggest that cholestasis, associated with the failure to achieve drainage of primary BAs, accelerates the progression of LM by remodeling the tumor immune microenvironment. Moreover, targeting BA anabolism with OCA may represent a therapeutic strategy for cholestasis-associated LM of colorectal cancer.
2024-07-10 | GSE209836 | GEO
Project description:Metastasis occurs frequently after resection of pancreatic cancer (PC). We hypothesized that multiparametric analysis of pre-metastatic liver biopsies will classify patients according to their metastatic risk, timing, and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PC and 18 control patients with non-cancerous pancreatic lesions were analyzed combining metabolomic, tissue and single cell transcriptomics, and multiplex imaging approaches. Patients were followed prospectively (median three years) and classified into four recurrence groups; early (<6 months post resection) or late (>6 months post resection) liver metastasis (LM), extrahepatic (EH) metastasis, and disease-free survivors (NED). Overall, PC livers exhibited signs of augmented inflammation, compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation, and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LM were characterized by scant T cell lobular infiltration, less steatosis, and higher levels of citrullinated H3, compared to patients who developed EH metastasis, who had overexpression of interferon target genes (MX1, NR1D1) and an increase of CD11B+ NK cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B+ NK cells, differentiated patients with early-onset from those with late-onset LM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multiparametric profiling of liver biopsies at the time of PC diagnosis may determine metastatic risk and organotropism, and guide clinical stratification for optimal treatment selection.
2024-06-28 | GSE245535 | GEO
Project description:Colorectal adenocarcinomas (CRC) are one of the most commonly diagnosed tumors worldwide. Colorectal adenocarcinomas primarily metastasize into the liver and (less often) into the peritoneum. Patients suffering from CRC-liver metastasis (CRC-LM) typically present with a dismal overall survival compared to non-metastasized CRC patients. The metastasis process and metastasis promoting factors in patients with CRC are under intensive debate. However, CRC studies investigating the proteome biology are lacking. Formalin-fixed paraffin-embedded (FFPE) tissue specimens provide a valuable resource for comprehensive proteomic studies of a broad variety of clinical malignancies. The presented pilot study compares the proteome of primary CRC and patient-matched CRC-LM. The applied protocol allows a reproducible and straightforward identification and quantification of over 2,600 proteins within the dissected tumorous tissue. Subsequent unsupervised clustering reveals distinct proteome biologies of the primary CRC and the corresponding CRC-LM. Statistical analysis yields multiple differentially abundant proteins in either primary CRC or their corresponding liver metastases. A more detailed analysis of dysregulated biological processes suggests an active immune response in the liver metastases, including several proteins of the complement system. Proteins with structural roles, e.g. cytoskeleton organization or cell junction assembly appear to be less prominent in liver metastases as compared to primary CRC. Immunohistochemistry corroborates proteomic high expression levels of metabolic proteins in CRC-LM. We further assessed how the in vitro inhibition of two in CRC-LM enriched metabolic proteins affected cell proliferation and chemosensitivity. The presented proteomic investigation in a small clinical cohort promotes a more comprehensive understanding of the distinct proteome biology of primary CRC and their corresponding liver metastases.
| EGAS00001005641 | EGA
Project description:To find candidate circRNAs and to unravel their molecular functions during colorectal cancer progression and during LDM topotecan chemotherapy, we utilized a xenograft mouse model based on the HT29.hCG.Luc colorectal cancer cell line (referred to as HT29) implanted into SCID mice. HT29 cells were injected into the spleen and primary tumors developed. Three mice served as control group while two mice served as LDM topotecan treated group. After another 4-6 weeks, liver metastasis can be detected and resected for further investigation. For a global view on miRNA changes, we performed miRNA-Seq from HT29 cells, primary tumors and liver metastases from control mice (C-PT and C-LM) and liver metastases from treated mice (T-LM).
2021-01-13 | GSE163074 | GEO
Project description:To investigate genomic plasticity over time associated with response to standard chemotherapy, we collected longitudinal liver metastasis (LM) samples from 155 patients and characterized the copy number aberration (CNA) landscape and its effect on the transcriptome. CNA profiles of lesions exhibiting different treatment response were compared and focal genomic divergences reported. By investigating genomic-phenotype associations of the largest reported LM cohort to date, we identified novel molecular features associated with drug response supporting the relevance of collecting clinical metastatic samples.
2021-06-23 | GSE152178 | GEO
Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Treatment of HCC remains abysmal; discovery of novel pathways implicated in hepatocarcinogenesis is needed for more effective therapeutics. SALL4 is a stem cell factor essential for the maintenance of embryonic stem cell self-renewal properties and expressed in fetal liver, but silenced in normal adult liver. We observed that expression of SALL4 in murine liver in a transgenic model led to development of HCC. In humans, SALL4 is re-expressed as an oncofetal protein in a subgroup of HCC patients with unfavorable prognoses. Loss-of-function studies demonstrated that SALL4 is essential for human HCC cell survival and tumorigenicity. We demonstrated that a peptide can block the oncogenic function of SALL4 in HCC by modulating the PTEN/AKT pathway. Our findings reveal a novel role of SALL4 in HCC with important implications for understanding disease mechanisms and development of innovative therapeutics. Cultured cells from HCC cell line SNU-398 with scrambled or SALL4 shRNA knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.
2012-02-22 | E-GEOD-35965 | biostudies-arrayexpress
Project description:Liver metastasis (LM) is the primary cause of cancer-related mortality in late-stage breast cancer (BC) patients. However, the complexity and diversity of the tumor microenvironment (TME) of LM have not been fully understood. Here we report an in-depth analysis of the transcriptional landscape of liver metastases of 11 patients with secondary hepatic carcinoma at single-cell resolution. Our study reveals that terminally exhausted CD4+ and dysfunctional CD8+ T cells were enriched in metastatic tumor along with low antigen presentation. We also found macrophages were associated with the infiltration profile of CD4+ T cells, while FCN3+ macrophages, type 1 conventional dendritic cells (cDC1) and LAMP3+ DC regulated T cell functions, probably via antigen processing and presentation. MHC expression in FCN3+ macrophage, cDC1 and LAMP3+ DC was reduced in LM compared to those in normal tissues and primary tumor of BC. Dysfunction of antigen presentation in these cells is linked to a worse prognosis in breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC) cohorts and identifies potentially targetable immune inhibitory pathways in secondary hepatic carcinoma. Thus, our results show a cellular diversity of TME in BC-LM, providing valuable insights into the role of tumor infiltrating T cells in liver metastatic cancers.
2024-01-23 | GSE249361 | GEO
Project description:Gastric cancer (GC) is one of the most frequent and lethal malignancies in the world. However, our understanding of the mechanisms underlying its initiation and progression is limited. Here, we applied genome-edited gastric organoids to establish a series of primary GC models in mice, which elucidated the genetic drivers for sequential transformation from dysplasia to well-differentiated and poorly differentiated GC. Further, we found that the orthotopic GC, but not the subcutaneous GC even with the same genetic drivers, displayed remote metastasis, suggesting critical roles of the microenvironment in GC metastasis. Through single-cell RNA-seq analyses and functional studies, we revealed that the molecular interaction between fibronectin 1 on stomach-specific macrophages and integrin α6β4 on GC cells promoted liver metastasis. Taken together, our studies proposed a new strategy to model GC and dissected the genetic and microenvironmental factors driving the full-range gastric tumorigenesis.
2022-09-05 | GSE188761 | GEO