All-human microphysical model of metastasis therapy

Sarah E. Wheeler, Jeffrey T. Borenstein, Amanda M. Clark, Mohammad Ebrahimkhani, Ira J. Fox, Linda Griffith, Walker Inman, Douglas Lauffenburger, Transon Nguyen, Venkateswaran C. Pillai, Rachelle Prantil-Baun, Donna B. Stolz, Donald Taylor, Theresa Ulrich, Raman Venkataramanan, Alan Wells, Carissa Young

Research output: Contribution to journalReview article

22 Citations (Scopus)

Abstract

The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development - particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses, is readily transferable to other organs, giving this work impact beyond the liver.

Original languageEnglish (US)
Article numberS11
JournalStem Cell Research and Therapy
Volume4
Issue numberSUPPL.1
DOIs
StatePublished - Dec 20 2013
Externally publishedYes

Fingerprint

Liver
Tumors
Neoplasm Metastasis
Bioreactors
Neoplasms
Metabolism
Therapeutics
Cells
Oxygen sensors
Monitoring
Xenobiotics
Nutrients
Neoplasm Micrometastasis
Hormones
Tissue
Sampling
Hepatocytes
Pharmaceutical Preparations
Pharmacology
Breast Neoplasms

Keywords

  • liver
  • mammary carcinoma
  • microenvironment
  • tumor dissemination

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Molecular Medicine
  • Cell Biology
  • Medicine (miscellaneous)

Cite this

Wheeler, S. E., Borenstein, J. T., Clark, A. M., Ebrahimkhani, M., Fox, I. J., Griffith, L., ... Young, C. (2013). All-human microphysical model of metastasis therapy. Stem Cell Research and Therapy, 4(SUPPL.1), [S11]. https://doi.org/10.1186/scrt372

All-human microphysical model of metastasis therapy. / Wheeler, Sarah E.; Borenstein, Jeffrey T.; Clark, Amanda M.; Ebrahimkhani, Mohammad; Fox, Ira J.; Griffith, Linda; Inman, Walker; Lauffenburger, Douglas; Nguyen, Transon; Pillai, Venkateswaran C.; Prantil-Baun, Rachelle; Stolz, Donna B.; Taylor, Donald; Ulrich, Theresa; Venkataramanan, Raman; Wells, Alan; Young, Carissa.

In: Stem Cell Research and Therapy, Vol. 4, No. SUPPL.1, S11, 20.12.2013.

Research output: Contribution to journalReview article

Wheeler, SE, Borenstein, JT, Clark, AM, Ebrahimkhani, M, Fox, IJ, Griffith, L, Inman, W, Lauffenburger, D, Nguyen, T, Pillai, VC, Prantil-Baun, R, Stolz, DB, Taylor, D, Ulrich, T, Venkataramanan, R, Wells, A & Young, C 2013, 'All-human microphysical model of metastasis therapy', Stem Cell Research and Therapy, vol. 4, no. SUPPL.1, S11. https://doi.org/10.1186/scrt372
Wheeler SE, Borenstein JT, Clark AM, Ebrahimkhani M, Fox IJ, Griffith L et al. All-human microphysical model of metastasis therapy. Stem Cell Research and Therapy. 2013 Dec 20;4(SUPPL.1). S11. https://doi.org/10.1186/scrt372
Wheeler, Sarah E. ; Borenstein, Jeffrey T. ; Clark, Amanda M. ; Ebrahimkhani, Mohammad ; Fox, Ira J. ; Griffith, Linda ; Inman, Walker ; Lauffenburger, Douglas ; Nguyen, Transon ; Pillai, Venkateswaran C. ; Prantil-Baun, Rachelle ; Stolz, Donna B. ; Taylor, Donald ; Ulrich, Theresa ; Venkataramanan, Raman ; Wells, Alan ; Young, Carissa. / All-human microphysical model of metastasis therapy. In: Stem Cell Research and Therapy. 2013 ; Vol. 4, No. SUPPL.1.
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abstract = "The vast majority of cancer mortalities result from distant metastases. The metastatic microenvironment provides unique protection to ectopic tumors as the primary tumors often respond to specific agents. Although significant interventional progress has been made on primary tumors, the lack of relevant accessible model in vitro systems in which to study metastases has plagued metastatic therapeutic development - particularly among micrometastases. A real-time, all-human model of metastatic seeding and cancer cells that recapitulate metastatic growth and can be probed in real time by a variety of measures and challenges would provide a critical window into the pathophysiology of metastasis and pharmacology of metastatic tumor resistance. To achieve this we are advancing our microscale bioreactor that incorporates human hepatocytes, human nonparenchymal liver cells, and human breast cancer cells to mimic the hepatic niche in three dimensions with functional tissue. This bioreactor is instrumented with oxygen sensors, micropumps capable of generating diurnally varying profiles of nutrients and hormones, while enabling real-time sampling. Since the liver is a major metastatic site for a wide variety of carcinomas and other tumors, this bioreactor uniquely allows us to more accurately recreate the human metastatic microenvironment and probe the paracrine effects between the liver parenchyma and metastatic cells. Further, as the liver is the principal site of xenobiotic metabolism, this reactor will help us investigate the chemotherapeutic response within a metabolically challenged liver microenvironment. This model is anticipated to yield markers of metastatic behavior and pharmacologic metabolism that will enable better clinical monitoring, and will guide the design of clinical studies to understand drug efficacy and safety in cancer therapeutics. This highly instrumented bioreactor format, hosting a growing tumor within a microenvironment and monitoring its responses, is readily transferable to other organs, giving this work impact beyond the liver.",
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