Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration

Manjulata Singh, Xiaojun Tian, Vera S. Donnenberg, Alan M. Watson, Jing Yu Zhang, Laura P. Stabile, Simon C. Watkins, Jianhua Xing, Shilpa Sant

Research output: Contribution to journalArticle

Abstract

Targeting microenvironmental factors that foster migratory cell phenotypes is a promising strategy for halting tumor migration. However, lack of mechanistic understanding of the emergence of migratory phenotypes impedes pharmaceutical drug development. Using our three-dimensional microtumor model with tight control over tumor size, we recapitulated the tumor size–induced hypoxic microenvironment and emergence of migratory phenotypes in microtumors from epithelial breast cells and patient-derived primary metastatic breast cancer cells, mesothelioma cells, and lung cancer xenograft cells. The microtumor models from various patient-derived tumor cells and patient-derived xenograft cells revealed upregulation of tumor-secreted factors, including matrix metalloproteinase-9 (MMP9), fibronectin (FN), and soluble E-cadherin, consistent with clinically reported elevated levels of FN and MMP9 in patient breast tumors compared with healthy mammary glands. Secreted factors in the conditioned media of large microtumors induced a migratory phenotype in nonhypoxic, nonmigratory small microtumors. Subsequent mathematical analyses identified a two-stage microtumor progression and migration mechanism whereby hypoxia induces a migratory phenotype in the initialization stage, which then becomes self-sustained through a positive feedback loop established among the tumor-secreted factors. Computational and experimental studies showed that inhibition of tumor-secreted factors effectively halts microtumor migration despite tumor-to-tumor variation in migration kinetics, while inhibition of hypoxia is effective only within a time window and is compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but does not sustain it. In summary, we show that targeting temporal dynamics of evolving microenvironments, especially tumor-secreted factors during tumor progression, can halt tumor migration. Significance: This study uses state-of-the-art three-dimensional microtumor models and computational approaches to highlight the temporal dynamics of tumor-secreted microenvironmental factors in inducing tumor migration.

Original languageEnglish (US)
Pages (from-to)2962-2977
Number of pages16
JournalCancer Research
Volume79
Issue number11
DOIs
StatePublished - Jun 1 2019

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Neoplasms
Phenotype
Matrix Metalloproteinase 9
Tumor Hypoxia
Fibronectins
Heterografts
Breast Neoplasms
Tumor Microenvironment
Mesothelioma
Cadherins
Human Mammary Glands
Conditioned Culture Medium
Pharmaceutical Preparations
Lung Neoplasms
Breast
Up-Regulation
Epithelial Cells
Hypoxia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Singh, M., Tian, X., Donnenberg, V. S., Watson, A. M., Zhang, J. Y., Stabile, L. P., ... Sant, S. (2019). Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration. Cancer Research, 79(11), 2962-2977. https://doi.org/10.1158/0008-5472.CAN-18-3151

Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration. / Singh, Manjulata; Tian, Xiaojun; Donnenberg, Vera S.; Watson, Alan M.; Zhang, Jing Yu; Stabile, Laura P.; Watkins, Simon C.; Xing, Jianhua; Sant, Shilpa.

In: Cancer Research, Vol. 79, No. 11, 01.06.2019, p. 2962-2977.

Research output: Contribution to journalArticle

Singh, M, Tian, X, Donnenberg, VS, Watson, AM, Zhang, JY, Stabile, LP, Watkins, SC, Xing, J & Sant, S 2019, 'Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration', Cancer Research, vol. 79, no. 11, pp. 2962-2977. https://doi.org/10.1158/0008-5472.CAN-18-3151
Singh, Manjulata ; Tian, Xiaojun ; Donnenberg, Vera S. ; Watson, Alan M. ; Zhang, Jing Yu ; Stabile, Laura P. ; Watkins, Simon C. ; Xing, Jianhua ; Sant, Shilpa. / Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration. In: Cancer Research. 2019 ; Vol. 79, No. 11. pp. 2962-2977.
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