Single-cell gene expression profiles of cells from primary colorectal cancer and adjacent normal tissue [scRNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE294300 | GEO | 2026/07/22
REPOSITORIES: GEO
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Project description:Abstract Objective: JianPiHuaTan Formula (JPHTF), a traditional Chinese medicine (TCM), has been utilized as an adjunctive therapy for colorectal cancer (CRC). The study aims to evaluate the potential clinical benefits of JPHTF and its effectiveness in inhibiting tumor growth. Methods: 300 stage II/III CRC patients and 412 advanced CRC patients were enrolled to verify the clinical value of JPHTF in CRC treatment. Furthermore, CRC patient-derived xenograft (PDX) mice were utilized to investigate the regulatory mechanisms of JPHTF. Results: JPHTF significantly improved abdominal distension, shortness of breath, drowsiness, loss of appetite, sleep, and tiredness in stage II/III CRC patients, thereby improving their quality of life. Simultaneously, JPHTF served as a supportive therapy in extending the overall survival (OS) of stage IV CRC patients with RAS/RAF mutations undergoing chemotherapy. Additionally, JPHTF effectively impeded tumor progression in CRC PDX models with RAS mutation, accompanied by a reduction in tumor cell content in the JPHTF group. Transcriptomic analysis revealed the involvement of the Hippo and Hedgehog signaling pathways in JPHTF-mediated CRC inhibition. Furthermore, mice in the JPHTF group exhibited increased immune cell infiltration. Conclusions: These findings suggested that JPHTF may inhibits tumor growth in CRC with RAS mutation by modulating RAS/RAF downstream signaling pathways, specifically the Hippo and Hedgehog signaling, leading to increased immune cell infiltration.
2024-06-15 | GSE269502 | GEO
Project description:Despite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (50 years old) and late onset (65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. We also performed gain of function experiments with CFD and SAA1 in subcutaneous tumor murine models and found that CFD is associated with higher tumor volumes, impacted several immune genes and impacted three genes in mice that were also found to be differentially expressed in early onset CRC (EGR1, PSMB9, CXCL9). Our data demonstrate that the immune microenvironment, characterized by a distinct innate immune response signature in early onset CRC, is unique, location dependent, and might contribute to worse outcomes.
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Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP
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2026-06-13 | GSE269456 | GEO
Project description:The Kirsten rat sarcoma (KRAS) gene is the most frequently mutated oncogene in colorectal cancer (CRC). We previously characterized two activating alleles of KRAS, A59T and A59E, that show impaired BRAF dimerization. These alleles of KRAS are enriched in CRC tumors with genetic alterations in genes that regulate MAPK signaling (e.g. EGFR, NF1). Using a new conditional mouse model of K-Ras (LSL-K-Ras A59E) we show that, despite its inability to universally activate RAF kinases, K-Ras A59E disturbs colon epithelium and decreases mouse survival in a tumor model. By combining LSL-K-Ras A59E mice with a conditional knockout of Nf1, we demonstrate cooperation between these alleles at multiple levels. Consistent with cooperation and clinical observations, we show that K-Ras A59E neither promotes EGF independence of organoid growth, nor confers intrinsic resistance to EGFR inhibition. Thus, our data provide a deeper understanding of the role of RAF isoforms in mutant KRAS driven CRC and argue for the use of anti-EGFR therapies against some Ala59 mutant alleles of KRAS.
2025-07-02 | GSE300614 | GEO
Project description:Liver metastasis is the leading cause of mortality in patients with colorectal cancer (CRC). Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in CRC liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multi-omics analysis of 130 samples from 18 synchronous CRLM patients integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of non-malignant cells between primary tumors from patients with metastatic CRC (mCRC) and non-metastatic CRC, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid-nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared to wild-type mice, while co-transfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in CRC patients. Additionally, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.
2024-01-05 | GSE245552 | GEO
Project description:Liver metastasis is the leading cause of mortality in patients with colorectal cancer (CRC). Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in CRC liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multi-omics analysis of 130 samples from 18 synchronous CRLM patients integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of non-malignant cells between primary tumors from patients with metastatic CRC (mCRC) and non-metastatic CRC, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid-nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared to wild-type mice, while co-transfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in CRC patients. Additionally, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.
2024-02-06 | GSE255165 | GEO
Project description:Liver metastasis is the leading cause of mortality in patients with colorectal cancer (CRC). Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in CRC liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multi-omics analysis of 130 samples from 18 synchronous CRLM patients integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of non-malignant cells between primary tumors from patients with metastatic CRC (mCRC) and non-metastatic CRC, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid-nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared to wild-type mice, while co-transfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in CRC patients. Additionally, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.
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Project description:Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors. The gene set enrichment analysis showed uniform upregulation in several metabolic gene sets and most immune gene sets including NK-mediated immunity and IL-12 pathway while the IL6 pathway was downregulated. While there were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention, we did identify functional overlap with treatment in both groups in proliferative, immune, and metabolic pathways. In the pre-treatment tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of exhausted-1 immune cells (defined as OX40-/AE1_AE3-/PD-L1- cells, positive for 1/3 exhaustion markers, LAG3 or CTLA4 or TIM3) was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved disease control with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).
2025-12-04 | GSE302918 | GEO
Project description:Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors. The gene set enrichment analysis showed uniform upregulation in several metabolic gene sets and most immune gene sets including NK-mediated immunity and IL-12 pathway while the IL6 pathway was downregulated. While there were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention, we did identify functional overlap with treatment in both groups in proliferative, immune, and metabolic pathways. In the pre-treatment tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of exhausted-1 immune cells (defined as OX40-/AE1_AE3-/PD-L1- cells, positive for 1/3 exhaustion markers, LAG3 or CTLA4 or TIM3) was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved disease control with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).
2025-12-03 | GSE302917 | GEO