Collagen remodeling in the hypoxic tumor- mesothelial niche promotes ovarian cancer metastasis

Suchitra Natarajan, Kaitlyn M. Foreman, Michaela I. Soriano, Ninna S. Rossen, Hussein Shehade, Daniel R. Fregoso, Joshua T. Eggold, Venkatesh Krishnan, Oliver Dorigo, Adam J. Krieg, Sarah C. Heilshorn, Subarna Sinha, Katherine C. Fuh, Erinn B. Rankin

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5 Scopus citations

Abstract

Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here, we report that the HGSOC tumor-mesothelial niche was hypoxic, and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC. Significance: This study identifies HIF/LOX signaling as a potential therapeutic target to inhibit collagen remodeling and tumor progression in HGSOC.

Original languageEnglish (US)
Pages (from-to)2271-2284
Number of pages14
JournalCancer Research
Volume79
Issue number9
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Natarajan, S., Foreman, K. M., Soriano, M. I., Rossen, N. S., Shehade, H., Fregoso, D. R., Eggold, J. T., Krishnan, V., Dorigo, O., Krieg, A. J., Heilshorn, S. C., Sinha, S., Fuh, K. C., & Rankin, E. B. (2019). Collagen remodeling in the hypoxic tumor- mesothelial niche promotes ovarian cancer metastasis. Cancer Research, 79(9), 2271-2284. https://doi.org/10.1158/0008-5472.CAN-18-2616