Gene expression profile of RAS/RAF–wild-type colorectal cancer patient-derived spheroids
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ABSTRACT:
PROVIDER: PRJNA781982 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16988605_1.fastq.gz | Fastqsanger.gz | |||
| SRR16988605_2.fastq.gz | Fastqsanger.gz | |||
| SRR16988606_1.fastq.gz | Fastqsanger.gz | |||
| SRR16988606_2.fastq.gz | Fastqsanger.gz | |||
| SRR16988607_1.fastq.gz | Fastqsanger.gz |
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Project description:Gene expression profile of RAS/RAF–wild-type colorectal cancer patient-derived spheroids II
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Project description:We would like to propose a novel parameter that helps predict the chemosensitivity of cancer patients to FGFR inhibitors (FGFRi). Although FGFRi were introduced into the clinical trials on a variety of cancer types, they were found to be particularly efficacious on urothelial cancer and on cholangiocarcinoma for which the FDA had approved several compounds based on clinical studies. The enrollment criteria in such clinical trials were genomic changes in the FGFR genes including amplifications, translocations that caused gene fusions, and point mutations. By scrutinizing the published data on these reports, we have noticed an unresolved issue. Namely, most of these reports showed waterfall plots where tumors of some good fractions of enrolled patients responded well, demonstrating efficacy of the FGFRi. Importantly, however, there were sizable subsets in which tumors did not respond to the FGFRi despite that the patients’ tumors carried the genomic changes that met the enrollment criteria. As already established, both FGFR and EGFR share the downstream signaling pathway of MAPK activation as well as other pathways. Accordingly, it is conceivable that chemotherapeutic inhibition of FGFR alone may leave the MAPK signaling unaffected when the signaling through EGFR is relatively strong. To test this hypothesis, we calculated the FGFR to EGFR mRNA ratio (F/E for short) based on the RNA sequencing data from the Broad Institute Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org/ccle) of cholangiocarcinoma and urothelial cancer cell lines for which FGFRi chemosensitivity had been published in preclinical studies. Because human FGFR has four paralogs FGFR1–4, we first summed up the expression levels of FGFR1–4 mRNAs by adding the read numbers per MB of FGFR paralogs (sumFGFR). To take EGFR expression into consideration, we then divided this number with that of EGFR; F/E. In six biliary tract cancer cell lines tested, two responsive cell lines had higher F/E ratios of 9.5 and 9.0, whereas four non-responsive lines had substantially lower ratios of 0.1–1.8. In 22 urothelial cancer cell lines, four of the five responsive lines showed F/E of 2.8–4.9, whereas 17 non-responsive lines had 0.01–2.7. To obtain further insights into the F/E ratio, we looked into our patient-derived colorectal cancer (CRC)-stem cell lines. Seven (28%) of 25 RAS/RAF-wild type CRC-stem cell lines responded to the pan-FGFRi erdafitinib singly in culture whereas 21 (84%) did respond to erdafitinib in combination with an EGFR inhibitor (erlotinib). The seven singly responsive cell lines showed relatively high F/E ranging 11–207 with the mean of 46, whereas the 18 non-responsive lines had the ratio of 3.5–37 with the mean at 12. These results suggest that F/E can be a useful biomarker also for colorectal cancer chemosensitivity where EGFR expression level can vary widely. Taken together, F/E is another strong predictor of responses to FGFRi that is as useful as the current genomic criteria that are based on the FGFR genomic changes.
2021-11-22 | GSE189212 | GEO
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:Fibroblast growth factor receptor inhibitors (FGFRi) were introduced into clinical trials on several cancer types and found to be particularly efficacious on urothelial cancer and cholangiocarcinoma. Although many enrolled patients responded well in clinical trials, there were some patients who did not respond to FGFRi despite that their tumors carried the genomic changes that met the enrollment criteria. As already established, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) share the downstream signaling pathway of MAPK activation. Accordingly, it is conceivable that chemotherapeutic inhibition of FGFR alone may leave the MAPK signaling unaffected when the signaling through EGFR is relatively strong. To test this hypothesis, we calculated the FGFR to EGFR mRNA ratio (F/E for short) of colorectal cancer stem cell (CRC-SC) spheroid, biliary-tract cancer, and urothelial cancer cell lines. As a result, CRC-SC spheroid and cancer cell lines responsive to FGFRi had higher F/E than non-responsive lines. In conclusion, we propose a novel parameter F/E as a biomarker that helps predict cancer chemosensitivity to FGFRi.
2022-08-31 | GSE205787 | GEO
Project description:The most common oncogenic mutations in multiple myeloma (MM) affect N- and K-RAS leading to constitutive activation of RAS-dependent signaling. Signal transduction via RAS, Raf and MAPK has been well described as a canonical pathway. In accordance with this assumption, we showed that the activity of the MEK/ERK module is strictly dependent on pan-Raf activity. However, inhibition of MEK/ERK has no or only minor effects on MM cell survival, whereas oncogenic Ras and pan-Raf critically contribute to survival of multiple myeloma cells. Therefore, we aimed to learn more about Raf-dependent but MEK-independent signaling effectors. We analyzed gene expression profiles in INA-6 cells after either pan-Raf inhibition with SB-590885 or MEK inhibition with PD-325901.
2016-11-21 | GSE75078 | GEO
Project description:Identifying dormant cells in colorectal cancer spheroids
| PRJNA454879 | ENA
Project description:Identification of K-Ras and B-Raf mutations in colorectal cancer (CRC) is essential to predict patients' response to anti-EGFR therapy and formulate appropriate therapeutic strategies to improve prognosis and survival. Here, we combined parallel reaction monitoring (PRM) with high-field asymmetric waveform ion mobility (FAIMS) to enhance mass spectrometry sensitivity and improve the identification of low-abundance K-Ras and B-Raf mutations in biological samples without immunoaffinity enrichment. In targeted LC-MS/MS analyses, FAIMS reduced the occurrence of interfering ions and enhanced precursor ion purity, resulting in a three-fold improvement in the detection limit for K-Ras and B-Raf mutated peptides. In addition, ion mobility separation of isomeric peptides using FAIMS facilitated the unambiguous identification of K-Ras G12D and G13D peptides. The application of targeted LC-MS/MS analyses using FAIMS is demonstrated for the detection and quantitation of B-Raf V600E, K-Ras G12D, G13D, and G12V in CRC cell lines and primary specimens.
2023-08-14 | PXD043799 | Pride
Project description:Identification of K-Ras and B-Raf mutations in colorectal cancer (CRC) is essential to predict patients' response to anti-EGFR therapy and formulate appropriate therapeutic strategies to improve prognosis and survival. Here, we combined parallel reaction monitoring (PRM) with high-field asymmetric waveform ion mobility (FAIMS) to enhance mass spectrometry sensitivity and improve the identification of low-abundance K-Ras and B-Raf mutations in biological samples without immunoaffinity enrichment. In targeted LC-MS/MS analyses, FAIMS reduced the occurrence of interfering ions and enhanced precursor ion purity, resulting in a three-fold improvement in the detection limit for K-Ras and B-Raf mutated peptides. In addition, ion mobility separation of isomeric peptides using FAIMS facilitated the unambiguous identification of K-Ras G12D and G13D peptides. The application of targeted LC-MS/MS analyses using FAIMS is demonstrated for the detection and quantitation of B-Raf V600E, K-Ras G12D, G13D, and G12V in CRC cell lines and primary specimens.
2023-11-20 | PXD047029 | Pride
Project description:The well-known hepatotoxicity mechanism resulting from alpha-amanitin (-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from -AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses. Bioinformatics analysis showed that AMA exposure increased protein phosphorylation in a time-dependent AMA AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of -AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by -AMA exposure followed by aberrant splicing events leading to cell death.
2023-03-11 | PXD035817 | Pride
Project description:The well-known hepatotoxicity mechanism resulting from alpha-amanitin (-AMA) exposure arises from RNA polymerase II (RNAP II) inhibition. RNAP Ⅱ inhibition occurs through the dysregulation of mRNA synthesis. However, the signaling pathways in hepatocytes that arise from -AMA have not yet been fully elucidated. Here, we identified that the RAS/RAF/ERK signaling pathway was activated through quantitative phosphoproteomic and molecular biological analyses. Bioinformatics analysis showed that AMA exposure increased protein phosphorylation in a time-dependent AMA AMA exposure. In addition, phosphorylation increased not only the components of the ERK signaling pathway but also U2AF65 and SPF45, known splicing factors. Therefore, we propose a novel mechanism of -AMA as follows. The RAS/RAF/ERK signaling pathway involved in aberrant splicing events is activated by -AMA exposure followed by aberrant splicing events leading to cell death.
2023-03-11 | PXD035758 | Pride