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 Krieg, Sarah C. Heilshorn, Subarna Sinha, Katherine C. Fuh, Erinn B. Rankin

Research output: Contribution to journalArticle

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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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Ovarian Neoplasms
Collagen
Protein-Lysine 6-Oxidase
Neoplasm Metastasis
Neoplasms
Fibrillar Collagens
Cell Hypoxia
Cellular Structures
Tumor Burden
Extracellular Matrix
Morbidity
Mortality

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., ... 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

Collagen remodeling in the hypoxic tumor- mesothelial niche promotes ovarian cancer metastasis. / Natarajan, Suchitra; Foreman, Kaitlyn M.; Soriano, Michaela I.; Rossen, Ninna S.; Shehade, Hussein; Fregoso, Daniel R.; Eggold, Joshua T.; Krishnan, Venkatesh; Dorigo, Oliver; Krieg, Adam; Heilshorn, Sarah C.; Sinha, Subarna; Fuh, Katherine C.; Rankin, Erinn B.

In: Cancer Research, Vol. 79, No. 9, 01.01.2019, p. 2271-2284.

Research output: Contribution to journalArticle

Natarajan, S, Foreman, KM, Soriano, MI, Rossen, NS, Shehade, H, Fregoso, DR, Eggold, JT, Krishnan, V, Dorigo, O, Krieg, A, Heilshorn, SC, Sinha, S, Fuh, KC & Rankin, EB 2019, 'Collagen remodeling in the hypoxic tumor- mesothelial niche promotes ovarian cancer metastasis', Cancer Research, vol. 79, no. 9, pp. 2271-2284. https://doi.org/10.1158/0008-5472.CAN-18-2616
Natarajan S, Foreman KM, Soriano MI, Rossen NS, Shehade H, Fregoso DR et al. Collagen remodeling in the hypoxic tumor- mesothelial niche promotes ovarian cancer metastasis. Cancer Research. 2019 Jan 1;79(9):2271-2284. https://doi.org/10.1158/0008-5472.CAN-18-2616
Natarajan, Suchitra ; Foreman, Kaitlyn M. ; Soriano, Michaela I. ; Rossen, Ninna S. ; Shehade, Hussein ; Fregoso, Daniel R. ; Eggold, Joshua T. ; Krishnan, Venkatesh ; Dorigo, Oliver ; Krieg, Adam ; Heilshorn, Sarah C. ; Sinha, Subarna ; Fuh, Katherine C. ; Rankin, Erinn B. / Collagen remodeling in the hypoxic tumor- mesothelial niche promotes ovarian cancer metastasis. In: Cancer Research. 2019 ; Vol. 79, No. 9. pp. 2271-2284.
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