Circulating tumor cells exhibit metastatic tropism and reveal brain metastasis drivers.

Journal: 
Cancer Discov
Publication Year: 
2019
Authors: 
Remi Klotz
Amal Thomas
Teng Teng
Sung Min Han
Oihana Iriondo
Lin Li
Sara Restrepo-Vassalli
Alan Wang
Negeen Izadian
Matthew MacKay
Byoung-San Moon
Kevin J Liu
Sathish Kumar Ganesan
Grace Lee
Diane S Kang
Charlotte S Walmsley
Christopher J Pinto
Michael F Press
Wange Lu
Janice Lu
Dejan Juric
Aditya Bardia
James Hicks
Bodour Salhia
Frank J Attenello
Andrew D Smith
Min Yu
PubMed link: 
31601552
Public Summary: 
Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTCs) 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 breast cancer patients 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 (SEMA4D) 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 breast cancer patients showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain
Scientific Abstract: 
Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTCs) 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 breast cancer patients 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 (SEMA4D) 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.