Increased YTHDF3 expression appears to be a key driver in brain metastases

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Approximately 200,000 cancer patients are diagnosed with brain metastases each year, yet few treatment options exist because the mechanisms that allow cancer to spread to the brain remain unclear.

However, a study recently published in the journal Cancer Cell by VCU Massey Cancer Center scientist Suyun Huang, M.D., Ph.D., offers hope for the development of future therapies by showing how a poorly understood gene known as YTHDF3 plays a significant role in the process.

Huang is renowned for her work in modeling the spread of cancer to the brain.

Her most recent findings show that increased YTHDF3 expression correlates with brain cancer metastases and poor survival outcomes in breast cancer patients. They also demonstrated that the gene is required for multiple steps in the brain metastatic process.

“This study could provide a marker to help doctors diagnose brain metastases early, as well as provide a target for the development of new drugs to prevent and treat brain metastases,” says Huang, a member of the Cancer Biology research program at Massey and professor in the Department of Human and Molecular Genetics at VCU School of Medicine.

Huang’s team discovered that breast cancer brain metastases have increased YTHDF3 gene copy numbers in comparison to primary breast tumors.

A gene’s copy number refers to the number of times it appears in the genome. Additional copies of YTHDF3 in metastatic tumor DNA show that mutations have occurred as the cancer cells replicated and spread.

Using a variety of techniques, the researchers profiled the gene to develop a comprehensive view of how it facilitates key processes for brain cancer metastasis through its role in the production of various proteins that interact with the brain microenvironment.

Through these experiments, they found that YTHDF3 contributed to the expression of a number of genes known to drive cancer development, including ST6GALNAC5, GJA1, EGFR and VEGFA. Mouse models lacking the YTHDF3 gene demonstrated prolonged survival and resistance to brain metastasis development.

“Now that we’ve shown how critical this gene is to the development of brain metastases, we plan to work on synthesizing drugs that can inhibit its function,” says Huang. “This is an urgent need, and we’re hopeful this research will eventually help save lives.”


StatusPublic on Sep 30, 2020
TitleYTHDF3 Induces the Translation of m6A-enriched Metastasis-associated Gene Transcripts to Promote Breast Cancer Brain Metastasis [RIP-Seq]
OrganismHomo sapiens
Experiment typeExpression profiling by high throughput sequencing
SummaryBrain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. We found that YTHDF3 overexpression clinically correlates with brain metastases in breast cancer patients and is required for brain metastasis. Silencing YTHDF3 suppressed the brain metastasis of breast cancer cells in vitro and in vivo. Integrated transcriptome and m6A-seq analysis revealed alter expression of selected YTHDF3 target genes, including ST6GALNAC5, GJA1, and EGFR by promoting m6A-dependent translation of these target transcripts. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby gaining brain metastatic competence.
 
Overall designOverall design: anti-YTHDF3 of mRNA from MDA-MB-231Br cells
 
Contributor(s)Huang SChang G
Citation missingHas this study been published? Please login to update or notify GEO.
Submission dateApr 23, 2019
Last update dateOct 01, 2020
Contact nameYouqiong Ye
E-mail(s)[email protected]
Phone+8613661565591
Organization nameShanghai Jiao Tong University School of Medicine
Street address280 Chongqing south road
CityShanghai
ZIP/Postal code200025
CountryChina


Huang collaborated on this study with Guoquiang Chang, Ph.D., and Peng Li, M.D., both from the Department of Human and Molecular Genetics at VCU School of Medicine; Lei Shi, Ph.D., Shweta Tiwary, Ph.D., Jason Huse, M.D., Ph.D., Lei Huo, M.D., Ph.D., Li Ma, Ph.D., Sicong Zhang, Ph.D., Jianwei Zhu and Lixian Zeng, all from MD Anderson Cancer Center; Victoria Xie from Baylor College of Medicine; Yongjie Ma, Ph.D., from Tianjin Medical Cancer Institute; Youqiong Ye, Ph.D., and Leng Han, Ph.D., from the University of Texas Health Science Center at Houston McGovern Medical School; and Hailing Shi, Ph.D., and Chuan He, Ph.D., from the University of Chicago.

Funding: This research was supported in part by National Institutes of Health grants RM1 HG008935 and 1R01CA198090, the Paul M. Corman, MD, Chair in Cancer research endowment fund, and VCU Massey Cancer Center’s National Cancer Institute Cancer Center Support Grant P30 CA016059.

Source: Virginia Commonwealth University

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