Metastatic Tumor-In-A-Dish, A Novel Multi-Cellular Organoid to Study Lung Colonization and Predict Therapeutic Response.

Paradigms and Technologies
Methods Development

Abstract

Metastasis is a major cause of cancer-related deaths. A dearth in preclinical models that recapitulates the metastatic microenvironment has impeded the development of therapeutic agents that are effective against metastatic disease. Since the majority of solid tumors metastasize to the lung, we developed a multi-cellular 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 2-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 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 that responded to therapy. Thus, we have developed a novel method for tumor 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.

Authors

Ramamoorthy, Prabhu; Thomas, Sufi Mary; Kaushik, Gaurav; Subramaniam, Dharmalingam; Chastain, Katherine M; Dhar, Animesh; Tawfik, Ossama; Kasi, Anup; Sun, Weijing; Ramalingam, Satish; Gunewardena, Sumedha; Umar, Shahid; Mammen, Joshua M V; Padhye, Subhash B; Weir, Scott J; Jensen, Roy A; Sittampalam, Sitta; Anant, Shrikant;

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