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Cancer Res. 2019 Apr 1;79(7):1681-1695. doi: 10.1158/0008-5472.CAN-18-2602. Epub 2019 Jan 23.

Metastatic Tumor-in-a-Dish, a Novel Multicellular Organoid to Study Lung Colonization and Predict Therapeutic Response.

Author information

1
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
2
Department of General Surgery, University of Kansas Medical Center, Kansas City, Kansas.
3
Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas.
4
Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.
5
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
6
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
7
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
8
Interdisciplinary Science and Technology Research Academy, University of Pune, Pune, Maharashtra, India.
9
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
10
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
11
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas. sanant@kumc.edu.

Abstract

Metastasis is a major cause of cancer-related deaths. A dearth of preclinical models that recapitulate the metastatic microenvironment has impeded the development of therapeutic agents that are effective against metastatic disease. Because the majority of solid tumors metastasize to the lung, we developed a multicellular lung organoid that mimics the lung microenvironment with air sac-like structures and production of lung surfactant protein. We used these cultures, called primitive lung-in-a-dish (PLiD), to recreate metastatic disease using primary and established cancer cells. The metastatic tumor-in-a-dish (mTiD) cultures resemble the architecture of metastatic tumors in the lung, including angiogenesis. Pretreating PLiD with tumor exosomes enhanced cancer cell colonization. We next tested the response of primary and established cancer cells to current chemotherapeutic agents and an anti-VEGF antibody in mTiD against cancer cells in two-dimensional (2D) or 3D cultures. The response of primary patient-derived colon and ovarian tumor cells to therapy in mTiD cultures matched the response of the patient in the clinic, but not in 2D or single-cell-type 3D cultures. The sensitive mTiD cultures also produced significantly lower circulating markers for cancer similar to that seen in patients who responded to therapy. Thus, we have developed a novel method for lung colonization in vitro, a final stage in tumor metastasis. Moreover, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects. SIGNIFICANCE: A lung organoid that exhibits characteristics of a normal human lung is developed to study the biology of metastatic disease and therapeutic intervention.

PMID:
30674533
PMCID:
PMC6445669
[Available on 2020-04-01]
DOI:
10.1158/0008-5472.CAN-18-2602

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