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Modulation of peritumoral fibroblasts with a membrane-tethered tissue inhibitor of metalloproteinase (TIMP) for the elimination of cancer cells

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Summary

Background. Peritumoral fibroblasts are key components of the tumor microenvironment. Through remodeling of the extracellular matrix (ECM) and secretion of pro-tumorigenic cytokines, peritumoral fibroblasts foster an immunosuppressive milieu conducive to tumor cell proliferation. In this study, we investigated if peritumoral fibroblasts could be therapeutically engineered to elicit an anti-cancer response by abolishing the proteolytic activities of membrane-bound metalloproteinases involved in ECM modulation. Methods. A high affinity, glycosylphosphatidylinositol (GPI)-anchored Tissue Inhibitor of Metalloproteinase (TIMP) named “T1PrαTACE” was created for dual inhibition of MT1-MMP and TACE. T1PrαTACE was expressed in fibroblasts and its effects on cancer cell proliferation investigated in 3D co-culture models. Results. T1PrαTACE abrogated the activities of MT1-MMP and TACE in host fibroblasts. As a GPI protein, T1PrαTACE could spontaneously detach from the plasma membrane of the fibroblast to co-localize with MT1-MMP and TACE on neighboring cancer cells. In a 3D co-culture model, T1PrαTACE promoted adherence between the cancer cells and surrounding fibroblasts, which led to an attenuation in tumor development. Conclusion. Peritumoral fibroblasts can be modulated with the TIMP for the elimination of cancer cells. As a novel anti-tumor strategy, our approach could potentially be used in combination with conventional chemo- and immunotherapies for a more effective cancer therapy.

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Data availability

All the data generated or analyzed during this study are included in this published article.

Abbreviations

ADAM:

A disintegrin and metalloproteinase

ECM:

Extracellular matrix

ELISA:

Enzyme-link immunosorbent assay

GFP:

Green fluorescent protein

HB-EGF-AP:

Heparin-binding epidermal growth factor alkaline phosphatase

IF:

Immunofluorescence

MMP:

Matrix metalloproteinase

MT1-MMP:

Membrane type 1-MMP

pNPP:

4-Nitrophenyl phosphate

RFP:

Red fluorescent protein

TACE:

TNF-α converting enzyme

TIMP:

Tissue inhibitor of metalloproteinase

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Acknowledgements

We thank the Suzhou Key Program Special Fund (grant KSF-E-11) and National Natural Science Foundation of China (NSFC grant 31270850) for their generous support of this study.

Funding

This work was supported by Suzhou Key Program Special Fund (grant KSF-E-11) and National Natural Science Foundation of China (NSFC grant 31270850).

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Authors and Affiliations

  1. Academy of Pharmacy, Xian Jiaotong Liverpool University, 111 Ren Ai Road, Suzhou Industrial Park, Suzhou, 215123, China

    Yihe Zhang, Shiyu Liu, Bingjie Jiang & Meng Huee Lee

  2. Pudong District, Shanghai XP Biomed Ltd, 3F Building 1, No. 80, Lane 1505, Zuchongzhi Rd, Shanghai, 201203, China

    Sung Kay Chiu

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  1. Yihe Zhang
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Contributions

Conception and design: M.H.L., Y.Z., S.L, S.K.C. and B.J. Development and methodology: B.J., Y.Z. and M.H.L. Acquisition of data: Y.Z., B.J., S.L., S.K.C. and M.H.L. Analysis and interpretation of data: Y.Z., B.J., S.L., S.K.C. and M.H.L. Writing and review of the manuscript: S.K.C. and M.H.L. Administrative, technical or material support: B.J.

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Correspondence to Meng Huee Lee.

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Zhang, Y., Liu, S., Jiang, B. et al. Modulation of peritumoral fibroblasts with a membrane-tethered tissue inhibitor of metalloproteinase (TIMP) for the elimination of cancer cells. Invest New Drugs 40, 198–208 (2022). https://doi.org/10.1007/s10637-021-01177-4

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  • DOI: https://doi.org/10.1007/s10637-021-01177-4

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