Engineering “self-homing” circulating tumour cells as novel cancer theranostics

Abstract

Purpose: New ways to target and treat metastatic disease are urgently needed. Tumor "selfhoming" describes the recruitment of circulating tumor cells (CTCs) back to a previously excised primary tumor location, contributing to tumor recurrence, as well as their migration to established metastatic lesions. Recently, self-homing CTCs have been exploited as delivery vehicles for anti-cancer therapeutics in preclinical primary tumor models. However, the ability of CTCs to self-home and treat metastatic disease is largely unknown. Methods: Here, we employ molecular imaging to explore whether systemically-administered CTCs home to metastatic lesions and if CTCs armed with both a reporter gene and a cytotoxic prodrug gene therapy can be used to visualize and treat metastatic disease. Results: Bioluminescence imaging (BLI) performed over time revealed a remarkable ability of CTCs to home to primary and metastatic tumors throughout the body. Mice that received therapeutic CTCs had less BLI signal as well as less primary tumour burden than control mice. Preliminary data also showed self-homing therapeutic CTCs may be effective at treating disseminated breast cancer metastases.Conclusion: Using dual-luciferase BLI, this study demonstrates the noteworthy ability of experimental CTCs to home to disseminated breast cancer lesions. Moreover, by incorporating a prodrug gene therapy system into our self-homing CTCs, we show exciting progress towards effective and targeted delivery of gene-based therapeutics to treat both primary and metastatic lesions.

Visualizing tumour self-homing with magnetic particle imaging

“…CTCs may represent a novel cell-based platform for therapy whereby, they are highly efficient at homing to established tumour sites, can be readily engineered and expanded ex vivo, and could be generated from an individual patient's tumour to avoid an unwanted immune response. Our group and others have shown exciting progress towards the development of selfhoming CTCs for the treatment of primary and metastatic lesions however, further study is warranted to optimize CTCs for clinical translation [3][4][5][6][7][8][9] . Here, we demonstrate for the first time, the In this work, we visualized iron-labeled MDA-MB-231BR-eGFP cells that had migrated to an MDA-MB-231 primary tumour, which we hypothesized may be due to a well-established tumour microenvironment.…”

“…Due to their tumour targeting capabilities, in recent years, self-homing CTCs have been repurposed as delivery vehicles for anticancer therapeutics. This has included the delivery of oncolytic viruses, pro-drug activatable suicide genes, and transgenes that alter the tumour microenvironment [3][4][5][6][7][8][9] . This strategy has shown exciting progress towards treating primary tumours, single organ metastases and most recently, multi-organ metastases however, further refinement is needed in order to optimize self-homing CTCs for potential clinical translation.…”

“…Cellular imaging can be used to noninvasively study a specific cell population or cellular process in vivo. Previous studies have used imaging reporter genes, namely bioluminescence imaging (BLI) 4,9 and positron emission tomography (PET) reporters 7,8 , to track CTCs in preclinical models.…”