Issue No. 33, October 2020
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.     
Genetic and Epigenetic Changes in YTHDF3 Promote Multiple Steps of Breast Cancer Brain Metastasis 
 
A recent discovery published in Cancer Cell by Dr. Suyun Huang and colleagues demonstrates that YTHDF3, an N6-methyladenosine (m6A) reader, is increased in breast cancer brain metastasis. It is required for multiple steps in the brain metastasis cascade, and may serve as a target for therapeutic intervention for life-threatening brain metastases.

  • GSE dataset analyses revealed that YTHDF3 expression is increased in breast cancer brain metastases and directly correlates with decreased brain metastasis-free survival in breast cancer patients.

  • YTHDF3 is indispensable for brain metastasis of breast cancer and its depletion impairs brain metastasis formation and prolongs mouse survival.

  • YTHDF3 promotes brain endothelial adhesion, extravasation, invasion, cancer cell-astrocyte interaction and angiogenesis during breast cancer brain metastasis.

  • Using RPPA (Reverse-Phase Protein Array), RNA immunoprecipitation sequencing (RIP-Seq), and m6A methylome profiling, ST6GALNAC5, GJA1, EGFR and VEGFA were identified as functionally essential targets of YTHDF3.

  • YTHDF3 promoted the translation of ST6GALNAC5, GJA1, EGFR and VEGFA in breast cancer brain metastases that depended on the binding of YTHDF3 to m6A-modified mRNA.

  • The copy-number of YTHDF3 gene is higher in breast cancer brain metastases than primary breast tumors and YTHDF3 autoregulates its translation by binding to m6A residues within its own 5’-UTR.
 
Brain metastasis occurs in more than 20% of all cancer patients, with approximately 200,000 occurrences in the United States each year. Fifteen to thirty percent of breast cancer patients develop brain metastasis, and the severity of this disease correlates with an extremely low survival rate. The high incidence of brain metastasis and its impact on survival presents a critical unmet need requiring an improved understanding of mechanisms and new treatments. New research from Dr. Huang and colleagues published in Cancer Cell* uncovers YTHDF3-mediated translation as a previously unidentified mechanism that drives the upregulation of key brain metastatic proteins and leads to interactions with the brain microenvironment, thereby facilitating breast cancer brain metastasis.
 
The results of the study* indicate that YTHDF3, a m6A reader, is increased in breast cancer brain metastasis than in primary breast tumors and correlates with decreased brain metastasis-free survival in breast cancer patients. To investigate the molecular mechanisms of YTHDF3 function in brain metastasis, reverse-phase protein array (RPPA) and RNA immunoprecipitation sequencing (RIP-seq) were used to identify the targets of YTHDF3 (Figure 1, left). Translation of ST6GALNAC5, GJA1, EGFR and VEGFA is induced by YTHDF3, and is dependent on the binding of YTHDF3 to m6A-modified mRNA at multiple steps of breast cancer brain metastasis including brain endothelial adhesion, extravasation, invasion, cancer cell-astrocyte interaction and angiogenesis (Figure 1, right). This study reveals that YTHDF3 upregulation is required for multiple steps of the brain metastasis cascade, and YTHDF3 could provide a novel therapeutic target for life-threatening brain metastases.

The results of the study* indicate that YTHDF3, a m6A reader, is increased in breast cancer brain metastasis than in primary breast tumors and correlates with decreased brain metastasis-free survival in breast cancer patients. To investigate the molecular mechanisms of YTHDF3 function in brain metastasis, reverse-phase protein array (RPPA) and RNA immunoprecipitation sequencing (RIP-seq) were used to identify the targets of YTHDF3 (Figure 1, left). Translation of ST6GALNAC5, GJA1, EGFR and VEGFA is induced by YTHDF3, and is dependent on the binding of YTHDF3 to m6A-modified mRNA at multiple steps of breast cancer brain metastasis including brain endothelial adhesion, extravasation, invasion, cancer cell-astrocyte interaction and angiogenesis (Figure 1, right). This study reveals that YTHDF3 upregulation is required for multiple steps of the brain metastasis cascade, and YTHDF3 could provide a novel therapeutic target for life-threatening brain metastases.
Figure 1. Left, Schematic workflow of YTHDF3 downstream targets analysis. Right: YTHDF3 promoted the translations of ST6GALNAC5, GJA1, EGFR and VEGFA in breast cancer brain metastasis dependent on the binding of YTHDF3 to m6A-modified mRNA.
Dr. Guoqiang Chang, a scientist in the Department of Human and Molecular Genetics at Virginia Commonwealth University, School of Medicine is the first author of this paper and performed much of the biological and animal work. The present study was supported in part by US NIH grants RM1 HG008935, and 1R01CA198090, and by Paul M. Corman, MD Chair in Cancer Research endowment fund.

Publication:

 
About the Investigators: Suyun Huang, MD, PhD, is a Professor of Human and Molecular Genetics (HMG), member of the VCU Institute of Molecular Medicine (VIMM) and Paul M. Corman, MD Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Chuan He, PhD, is Professor of Department of Chemistry and Institute for Biophysical Dynamic, Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biology, The University of Chicago. Guoqiang Chang, and Peng Li are scientists in HMG. Lei Shi, Lixian Zeng, Shweta Tiwary, Jason T. Huse, Lei Huo, Li Ma, Sicong Zhang, Jianwei Zhu are from UT MD Anderson Cancer Center. Youqiong Ye and Leng Han are from the Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School. Hailing Shi is from the Department of Chemistry and Institute for Biophysical Dynamic and Department of Biochemistry and Molecular Biology, The University of Chicago.