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Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

Author

Listed:
  • Tatiana Hurtado de Mendoza

    (Sanford-Burnham-Prebys Medical Discovery Institute)

  • Evangeline S. Mose

    (University of California)

  • Gregory P. Botta

    (Sanford-Burnham-Prebys Medical Discovery Institute
    University of California
    Scripps Research Translational Institute)

  • Gary B. Braun

    (Sanford-Burnham-Prebys Medical Discovery Institute)

  • Venkata R. Kotamraju

    (Sanford-Burnham-Prebys Medical Discovery Institute)

  • Randall P. French

    (University of California)

  • Kodai Suzuki

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Norio Miyamura

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Tambet Teesalu

    (Sanford-Burnham-Prebys Medical Discovery Institute
    University of California Santa Barbara
    University of Tartu)

  • Erkki Ruoslahti

    (Sanford-Burnham-Prebys Medical Discovery Institute
    University of California Santa Barbara)

  • Andrew M. Lowy

    (University of California)

  • Kazuki N. Sugahara

    (Sanford-Burnham-Prebys Medical Discovery Institute
    Columbia University Vagelos College of Physicians and Surgeons)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when β5 integrins are knocked out in the tumor cells. Of note, β5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high β5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.

Suggested Citation

  • Tatiana Hurtado de Mendoza & Evangeline S. Mose & Gregory P. Botta & Gary B. Braun & Venkata R. Kotamraju & Randall P. French & Kodai Suzuki & Norio Miyamura & Tambet Teesalu & Erkki Ruoslahti & Andre, 2021. "Tumor-penetrating therapy for β5 integrin-rich pancreas cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21858-1
    DOI: 10.1038/s41467-021-21858-1
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