Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers

Remi Klotz ^1 2, Amal Thomas ^# 3, Teng Teng ^# 1 2, Sung Min Han ^1 2, Oihana Iriondo ^1 2, Lin Li ^1 2, Sara Restrepo-Vassalli ⁴, Alan Wang ^1 2, Negeen Izadian ^1 2 5, Matthew MacKay ^1 2, Byoung-San Moon ^1 6, Kevin J Liu ^1 2, Sathish Kumar Ganesan ^1 2, Grace Lee ^1 2, Diane S Kang ^1 2, Charlotte S Walmsley ⁷, Christopher Pinto ⁷, Michael F Press ^2 8, Wange Lu ^1 6, Janice Lu ², Dejan Juric ⁷, Aditya Bardia ⁷, James Hicks ⁴, Bodour Salhia ^2 9, Frank Attenello ¹⁰, Andrew D Smith ³, Min Yu ^11 2Affiliations expand

• PMID: 31601552
• PMCID: PMC6954305
• DOI: 10.1158/2159-8290.CD-19-0384

Free PMC article

Abstract

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo-cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.This article is highlighted in the In This Issue feature, p. 1.

©2019 American Association for Cancer Research.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954305/

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