All-Human Microphysical Model of Metastasis Therapy Successful eradication of metastatic disease remains the grand challenge in reducing mortality from solid tumors. Although ablative approaches are infrequently possible, systemic chemotherapy usually is the only feasible option for inhibiting progression and increasing survival time, though it is rarely curative. Our understanding of why chemotherapeutic agents fail to eliminate metastases, and our ability to create more effective therapeutic strategies, is limited by both our deficit in dissecting the tumor-host interactions at a molecular and cellular level, and a lack of relevant model systems to screen novel therapies;and a dearth of all human systems to do this in a relevant manner. There is evidence that the tumor cells are affected by the metastatic micro-environment to become more resistant to chemotherapy and that chemotherapeutic metabolism is altered in the face of metastatic disease. We propose a system that will not only provide an all human contextual metastatic micro-environment, but one that is intimately linked to drug metabolism and to normal physiological functions of liver that may hinder or augment the efficacy or toxicities of therapies. More than any other common site of metastasis, the liver experiences dramatic swings in metabolic and hormonal state throughout the day. The extent to which these fluctuations influence malignant behaviors and chemotherapy responses in metastatic tumors is unknown. In this project we capture the complexity of this situation in vitro in a format amenable to incorporation in the drug development pipeline, using a 3D micro- perfused organotypic liver in a multiwell plate format. Our approach is designed to foster development of relatively large, clinically relevant metastatic nodules (>0.5 mm) in functional host liver tissue. We will (i) determine whether cyclic/diurnal changes in hormones, cytokines and nutrients delivered to tumor cells within host liver tissue alters the phenotypic behavior of the tumor cells compared to standard culture, such as proliferation, invasive properties, and expression of specific tumor markers;(ii) Determine whether the efficacy of chemotherapy agents against metastatic tumors is influenced by diurnal control of metabolism and hormones, using a panel of human tumor cells within the liver metastatic microenvironment and both general chemotherapeutics (metabolized and non-metabolized agents) and a targeted bio-therapeutics (in the kinase inhibitor class) and if so, if these are related to properties of the tumor that can be measured in situ (iii) Assess whether the chemotherapeutic toxicities on the liver are altered by metastatic involvement or by cyclical/diurnal variations in the liver affluent (iv) Test the hypothesis that mild inflammatory states of liver stimulate tumor growth and alter efficacy of chemotherapeutics.

Public Health Relevance

Carcinoma morbidity and mortality result overwhelmingly from the dissemination of the tumor beyond the initial site of development, to not only avoid directed surgical and radiological removal but also appear as more resistant to systemic therapies than the primary tumor. Development of new approaches that are obviously needed for these disseminated carcinoma cells is stymied by our dearth of knowledge concerning the tumor biology and how chemotherapy is metabolized in the metastatic niche, particularly in response to cyclic and diurnal rhythms of hormones, nutrients and inflammatory signals. Current in vitro models fail to capture the complexity of the microenvironment, and whole animal models do not allow for real time and continuous monitoring of the events and cell behaviors during the critical first month of establishment. Bioreactors offer a unique window into this period;we propose to develop a next generation all human liver bioreactor that provides physiologic mimicry of the human situation to aid in drug development and therapeutic approaches to metastasized cancers.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
4UH3TR000496-03
Application #
8768901
Study Section
Special Emphasis Panel (ZRG1-BST-N (50))
Program Officer
Tagle, Danilo A
Project Start
2012-07-24
Project End
2017-06-30
Budget Start
2014-09-06
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$1,045,766
Indirect Cost
$168,586
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Beckwitt, Colin H; Clark, Amanda M; Wheeler, Sarah et al. (2018) Liver 'organ on a chip'. Exp Cell Res 363:15-25
Beckwitt, Colin H; Brufsky, Adam; Oltvai, Zoltán N et al. (2018) Statin drugs to reduce breast cancer recurrence and mortality. Breast Cancer Res 20:144
Ishikawa, Takuro; Hosaka, Yoshinao Z; Beckwitt, Colin et al. (2018) Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics. Oncotarget 9:29304-29315
Clark, Amanda M; Kumar, Manu P; Wheeler, Sarah E et al. (2018) A Model of Dormant-Emergent Metastatic Breast Cancer Progression Enabling Exploration of Biomarker Signatures. Mol Cell Proteomics 17:619-630
Khazali, Ahmad S; Clark, Amanda M; Wells, Alan (2018) Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy. Br J Cancer 118:566-576
Beckwitt, Colin H; Shiraha, Keisuke; Wells, Alan (2018) Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling. PLoS One 13:e0197422
Maass, Christian; Dallas, Matthew; LaBarge, Matthew E et al. (2018) Establishing quasi-steady state operations of microphysiological systems (MPS) using tissue-specific metabolic dependencies. Sci Rep 8:8015
Raghu, Vineet K; Beckwitt, Colin H; Warita, Katsuhiko et al. (2018) Biomarker identification for statin sensitivity of cancer cell lines. Biochem Biophys Res Commun 495:659-665
Tsamandouras, Nikolaos; Chen, Wen Li Kelly; Edington, Collin D et al. (2017) Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies. AAPS J 19:1499-1512
Dioufa, Nikolina; Clark, Amanda M; Ma, Bo et al. (2017) Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells. Mol Cancer 16:172

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