Single-Cell Analysis Reveals Cellular Reprogramming in Advanced Colon Cancer Following FOLFOX-Bevacizumab Treatment
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PROVIDER: PRJNA972665 | ENA |
REPOSITORIES: ENA
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Project description:The combination of FOLFOX and bevacizumab (FOLFOX-Bev) is a promising treatment for advanced colorectal cancer (CRC). To gain insights into the cellular changes associated with FOLFOX-Bev treatment, we conducted single-cell transcriptomic analysis of CRC samples derived from a patient before and after treatment. Our results show that cancer cells with high proliferative, metastatic, and pro-angiogenic properties respond better to FOLFOX-Bev treatment. Moreover, FOLFOX-Bev enhances CD8+ T cell cytotoxicity, thereby boosting the anti-tumor immune response. Conversely, FOLFOX-Bev impairs the functionality of tumor-associated macrophages, plasma cells, and cancer-associated fibroblasts, leading to a decrease in VEGFB-mediated angiogenesis. Furthermore, FOLFOX-Bev treatment reset intercellular communication, which could potentially affect the function of non-cancer cells. Our findings provide valuable insights into the molecular mechanisms underlying the response of advanced CRC to FOLFOX-Bev treatment and highlight potential targets for improving the efficacy of this treatment strategy.
2023-07-20 | GSE232525 | GEO
Project description:IntroductionThe combination of FOLFOX and bevacizumab (FOLFOX-Bev) is a promising treatment for advanced colorectal cancer (CRC). However, the response of the tumor microenvironment to FOLFOX-Bev is still largely unexplored.MethodsWe conducted single-cell transcriptomic analysis of CRC samples derived from a patient before and after treatment to gain insights into the cellular changes associated with FOLFOX-Bev treatment.ResultsWe found that cancer cells with high proliferative, metastatic, and pro-angiogenic properties respond better to FOLFOX-Bev treatment. Moreover, FOLFOX-Bev enhances CD8+ T cell cytotoxicity, thereby boosting the anti-tumor immune response. Conversely, FOLFOX-Bev impairs the functionality of tumor-associated macrophages, plasma cells, and cancer-associated fibroblasts, leading to a decrease in VEGFB-mediated angiogenesis. Furthermore, FOLFOX-Bev treatment reset intercellular communication, which could potentially affect the function of non-cancer cells.DiscussionOur findings provide valuable insights into the molecular mechanisms underlying the response of advanced CRC to FOLFOX-Bev treatment and highlight potential targets for improving the efficacy of this treatment strategy.
| S-EPMC10421721 | biostudies-literature
Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. 18 tumor tissue samples were analysed, no replicates
2013-12-18 | E-GEOD-53127 | biostudies-arrayexpress
Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.
2013-12-18 | GSE53127 | GEO
Project description:Purpose: To study the potential priming benefit of bevacizumab from subsequent immunotherapy (durvalumab) in advanced breast cancer patients Methods: We tested this hypothesis by adding durvalumab after progression to maintenance single-agent bevacizumab treatment in advanced HER2-negative patients (average 3 treatment lines). In order to study the potential priming benefit, patients had to experience disease progression while on bevacizumab maintenance prior to entering the trial. In addition, we sought to find traits in peripheral-blood mononuclear cells (PBMCs) and tumor biopsies that informed about this immuno-priming, in an attempt to search for novel biomarkers of efficacy of the combo and obtain a better understanding of the biology of this clinical scenario. Results: Patients that experienced clinical benefit, compared with the remaining patients, displayed a lymphocyte pattern in PBMCs consisting on increased T-effector subpopulations (CD4- and CD8- effector and effector-memory) and decreased immunosuppressive T-regulatory cells. Gene-expression studies in tumor samples showed a congruent pattern, with increased T-effector and memory T cell signatures in responders, and increased T-regulatory and decreased active dendritic cells in non-responders. These events were observed in patients that displayed vascular normalization features as a result of previous bevacizumab, supporting the immuno-priming effects of this strategy.
2020-10-15 | GSE139050 | GEO
Project description:Response rates of 118 colorectal cancer patients to regiments were evaluated by histoculture drug response assay. Affymetrix SNP 6.0 chips were used to determine genotypes of the same colorectal cancer patients. SNPs associated with chemosensitivity to treatment regiments were identified by genome-wide association study. AV: avastin (Bevacizumab), ER: Erbitux (Cetuximab), FXA: bevacizumab + FOLFOX, FXE: Cetuximab + FOLFOX , FRA: Bevacizumab + FOLFIRI, FRE: Cetuximab + FOLFIRI; Numbers (0-100) represent responsiveness to the given drug regimens; the larger, the better responsive to given regimens
2011-03-25 | GSE21228 | GEO
Project description:Comparison the mRNA expression profiles of 101 CRC tissues to those from matched 35 non-neoplastic colon mucosal tissues from patients with stage III CRCs treated with FOLFOX adjuvant chemotherapy in each molecular subtype. Gene expression–based subtyping is widely accepted as a relevant source of disease stratification. Results provide important information of molecular marker genes for molecular classification.
2017-05-31 | GSE83889 | GEO
Project description:Microarrays were used to determine the efficacy of bevacizumab (a monoclonal antibody against the vascular endothelial growth factor and its receptors.) on endometrial cancer cells. Endometrial cancer is the most frequent gynecologic cancer in women. Long term outcomes for patients with advanced stage or recurrent disease are poor. Targeted molecular therapy against the vascular endothelial growth factor (VEGF) and its receptors constitute a new therapeutic option for these patients. The goal of our work was to assess the potential effectiveness of inhibition of VEGF/VEGFR signaling in a xenograft model of endometrial cancer using bevacizumab (Avastin, a humanized antibody against VEGFA). We also aimed to identify molecular markers of sensitivity or resistance to this agent. We show that bevacizumab retards tumor growth in athymic mice by inhibiting molecular components of signaling pathways that sustain cell survival and proliferation. We also demonstrate that resistance to bevacizumab may involve up-regulation of antiapoptotic genes and certain proto-oncogenes.
2009-09-22 | GSE18195 | GEO
Project description:Microarrays were used to determine the efficacy of bevacizumab (a monoclonal antibody against the vascular endothelial growth factor and its receptors.) on endometrial cancer cells. Endometrial cancer is the most frequent gynecologic cancer in women. Long term outcomes for patients with advanced stage or recurrent disease are poor. Targeted molecular therapy against the vascular endothelial growth factor (VEGF) and its receptors constitute a new therapeutic option for these patients. The goal of our work was to assess the potential effectiveness of inhibition of VEGF/VEGFR signaling in a xenograft model of endometrial cancer using bevacizumab (Avastin, a humanized antibody against VEGFA). We also aimed to identify molecular markers of sensitivity or resistance to this agent. We show that bevacizumab retards tumor growth in athymic mice by inhibiting molecular components of signaling pathways that sustain cell survival and proliferation. We also demonstrate that resistance to bevacizumab may involve up-regulation of antiapoptotic genes and certain proto-oncogenes. Experiment Overall Design: Human xenografts produced from endometrial cell line, grown in athymic mice, were treated in vivo with bevacizumab.
2009-11-16 | E-GEOD-18195 | biostudies-arrayexpress
Project description:This study aimed to identify potential miRNA-based biomarkers that can predict FOLFOX-CIPN symptoms. High throughput microRNA sequencing was performed on the RNA circulating in the plasma of eight patients with CRC who underwent FOLFOX chemotherapy. miRNA expression profiles were evaluated according to two groups: those who underwent ≤three cycles and those who underwent ≥six cycles of FOLFOX chemotherapy.
2024-03-06 | GSE260661 | GEO