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Updated: Jul 18, 2025
Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts
Published on: April 29, 2014
Multi-omic profiling and real time ex vivo modelling of imatinib-resistant dermatofibrosarcoma protuberans with
Jason Yongsheng Chan1,2,3, Elizabeth Chun Yong Lee4, Zhimei Li4
1Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. jason.chan.y.s@nccs.com.sg.
Abstract:
Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma, with the risk of aggressive fibro-sarcomatous transformation. Limited effective options are available for un-resectable or metastatic DFSP beyond targeting the oncogenic PDGF pathway with imatinib therapy. We established a patient-derived xenograft (PDX) and cell line model (designated MDFSP-S1) of imatinib-resistant DFSP with fibro-sarcomatous transformation. Whole genome sequencing identified high-level amplification at chromosomes 17 and 22, whilst homozygous deep deletion was demonstrated at chromosome 9 (CDKN2A, CDKN2B, MTAP). RNA sequencing followed by Sanger sequencing confirmed the pathognomonic COL1A1-PDGFB t (17;22) rearrangement in the original tumour, PDX and cell line model. Immunohistochemistry profiles of the PDX model were consistent with the patient's tumour sample (CD34 + /MIB1 + /SOX10- ). Gene set enrichment analysis highlighted top-scoring Hallmark gene sets in several oncogenic signalling pathways, including potentially targetable MTORC1 signalling and angiogenesis pathways. Antiangiogenic agents (sunitinib, regorafenib, pazopanib, axitinib) and the third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib exhibited modest anti-proliferative activity in the cell line, with IC50 values between 1 and 10 µM at 72 h. No significant activity was observed with imatinib, palbociclib, everolimus, olaparib, gefitinib and erlotinib (IC50 all > 10 µM). In conclusion, we established MDFSP-S1, a new PDX and cell line model of imatinib-resistant DFSP with fibro-sarcomatous transformation.
Insights
Researchers developed a new cell line model (MDFSP-S1) for studying imatinib-resistant dermatofibrosarcoma protuberans (DFSP) with aggressive transformation. This model aids in exploring novel therapeutic strategies for advanced DFSP.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer with limited treatment options for advanced stages.
- Imatinib targets the PDGF pathway but resistance is a significant clinical challenge.
- Fibro-sarcomatous transformation in DFSP indicates a more aggressive disease course.
Purpose of the Study:
- To establish a patient-derived xenograft (PDX) and cell line model of imatinib-resistant DFSP with fibro-sarcomatous transformation.
- To characterize the genetic alterations and molecular pathways involved in this resistant DFSP subtype.
- To evaluate potential therapeutic targets and drug sensitivities in the new model.
Main Methods:
- Established a PDX and cell line (MDFSP-S1) from an imatinib-resistant DFSP patient.
- Performed whole genome and RNA sequencing to identify genetic mutations and rearrangements.
- Confirmed the COL1A1-PDGFB rearrangement and assessed immunohistochemistry profiles.
- Utilized gene set enrichment analysis to identify activated signaling pathways.
- Tested the anti-proliferative effects of various targeted therapies in vitro.
Main Results:
- The MDFSP-S1 model recapitulates imatinib-resistant DFSP with fibro-sarcomatous features.
- Key genetic findings include amplification at chromosomes 17 and 22, and deletion at chromosome 9 (CDKN2A/B/MTAP).
- The pathognomonic COL1A1-PDGFB t(17;22) rearrangement was confirmed.
- MTORC1 signaling and angiogenesis pathways were identified as potentially targetable.
- Antiangiogenic agents and osimertinib showed modest activity; imatinib and other targeted agents were ineffective.
Conclusions:
- The MDFSP-S1 model provides a valuable preclinical tool for studying imatinib-resistant DFSP.
- This model facilitates the investigation of novel therapeutic strategies targeting identified pathways.
- Findings suggest potential efficacy of antiangiogenic agents and EGFR inhibitors in specific DFSP contexts.
