Synergistic metalloproteinase-based remodeling of matrix by pancreatic tumor and stromal cells

Hong Cao, Li Qiang, Jing Chen, Katherine M. Johnson, Mark A. McNiven, Gina L. Razidlo

Research output: Contribution to journalArticlepeer-review

Abstract

The process by which tumor cells mechanically invade through the surrounding stroma into peripheral tissues is an essential component of metastatic dissemination. Matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) degradation plays an important role in this invasive process. Defining the contribution and interaction between these MMPs during invasion remains a key interest in the development of targeted anti-metastatic therapies. In this study we have utilized multiple different stromal fibroblasts and tumor cells to define the relative contributions between cancer cells and stromal cells during MMP-dependent matrix remodeling and pancreatic (PDAC) tumor cell invasion. We find that tumor cells co-cultured with the conditioned medium from stromal fibroblasts exhibited a substantial increase in invadopodial-based matrix degradation and transwell invasion. This increase is dependent on pro-MMP2 expressed and secreted by stromal fibroblasts. Further, the pro-MMP2 from the stromal fibroblasts is activated by MT1-MMP expressed on the tumor cells. Depletion of MT1-MMP, the known activator of MMP2, in tumor cells largely blocked matrix remodeling, even in the presence of stromal cell medium. In summary, these findings implicate an important interplay between MT1-MMP from tumor cells and MMP2 from fibroblasts as a key component for ECM remodeling and invasion.

Original languageEnglish (US)
Article numbere0248111
JournalPloS one
Volume16
Issue number3 March
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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