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Multi-omic profiling and real time ex vivo modelling of imatinib-resistant dermatofibrosarcoma protuberans with fibrosarcomatous transformation

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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.

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Funding

This work was supported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award (TA21jun-0005) and RTF Seed Fund (SEEDFD21jun-0002); SingHealth Duke-NUS Academic Medical Centre and Oncology ACP Sarcoma Research Fund (08-FY2020/EX/25-A96 and 08-FY2020/EX/75-A151).

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Authors and Affiliations

  1. Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore

    Jason Yongsheng Chan & Eileen Poon

  2. Cancer Discovery Hub, National Cancer Centre Singapore, Singapore, Singapore

    Jason Yongsheng Chan, Elizabeth Chun Yong Lee, Zhimei Li, Jing Yi Lee & Abner Herbert Lim

  3. Duke-NUS Medical School, Singapore, Singapore

    Jason Yongsheng Chan

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  1. Jason Yongsheng Chan
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  2. Elizabeth Chun Yong Lee
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  3. Zhimei Li
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  6. Eileen Poon
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Contributions

JYC generated the experimental data and drafted the manuscript; ECL, ZL and JYL performed the cell line and xenograft experiments; AHL performed bioinformatic analysis. EP provided patient samples and clinical data. JYC and EP conceived the study, interpreted the results, and revised the manuscript; and all authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Jason Yongsheng Chan or Eileen Poon.

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Conflict of interest

The authors declare no competing financial interests.

Ethical approval

Ethics approval from the SingHealth Centralized Institution Review Board was obtained for tissue collection and consent protocols (2010.426.B). Xenograft studies were conducted in compliance with animal protocols approved by the SingHealth Institutional Animal Care and Use Committee (IACUC) (2018/SHS/1371).

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Written informed consent from the patient for use of clinical data and bio-specimens was obtained in accordance with the Declaration of Helsinki.

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Chan, J.Y., Lee, E.C.Y., Li, Z. et al. Multi-omic profiling and real time ex vivo modelling of imatinib-resistant dermatofibrosarcoma protuberans with fibrosarcomatous transformation. Human Cell 36, 2228–2236 (2023). https://doi.org/10.1007/s13577-023-00974-8

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