STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation.

Mohini Singh,Naresh K Murty,Sheila K Singh,Neha Garg,Maleeha Qazi,Ahmed M Ali,David A Rosa,Carolynn C Arpin,Nicole Mcfarlane,Robin Hallett,David Bakhshinyan,Patrick T Gunning,Parvez Vora,Branavan Manoranjan,Chitra Venugopal,Mulu Geletu,Sujeivan Mahendram,Sina Haftchenary,John A Hassell,Rodolfo F Gómez‐Biagi ,Andrew M Lewis ,Tomáš Tokár ,Igor Jurišica ,Brent D G Page ,Ping‐Shan Lai

doi:10.18632/oncotarget.4742

Abstract

Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases.

Highlights

Metastases are the most common neoplasm to affect the adult central nervous system, occurring at a rate ten times greater than that of primary neural cancers [1]
Brain metastasis initiating cells (BMICs) isolated from human primary lung-derived brain metastasis samples BT478 and BT530 were propagated as tumorspheres in in tumor sphere medium (TSM)
The tumor-initiating capacity of both brain metastasis initiating cells (BMICs) lines used in this study was assessed through intracranial injections into NOD-SCID mice (Figure 1C), where both BMIC lines were capable of tumor formation with as few as 100 cells injected, though the tumour size and aggressiveness differed between both samples

Summary

Introduction

Metastases are the most common neoplasm to affect the adult central nervous system, occurring at a rate ten times greater than that of primary neural cancers [1]. Brain metastases (BM) occur late in the progression of the primary cancer, and are typically associated with poor patient prognosis and survival; even with multimodal www.impactjournals.com/oncotarget treatment, survival is only 4–12 months [2, 3]. Our previous work [11] established the identification of TICs in BM through intracranial xenotransplantation of BM from lung primary cancers. These cells exhibited properties similar to BTICs, and are indicative of a brain metastasis initiating cell (BMIC) population

Methods

Results

Conclusion