Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes
Name
nihms-1521636.pdf
Description
Accepted version
Size
3.03 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Rohani, Nazanin
Hao, Liangliang
Alexis, Maria S
Joughin, Brian A
Krismer, Konstantin
Moufarrej, Mira N
Soltis, Anthony R
Lauffenburger, Douglas A
Yaffe, Michael B
Burge, Christopher B
Date Issued
2019
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
© 2019 American Association for Cancer Research. Acidosis is a fundamental feature of the tumor microenvironment, which directly regulates tumor cell invasion by affecting immune cell function, clonal cell evolution, and drug resistance. Despite the important association of tumor microenvironment acidosis with tumor cell invasion, relatively little is known regarding which areas within a tumor are acidic and how acidosis influences gene expression to promote invasion. Here, we injected a labeled pH-responsive peptide to mark acidic regions within tumors. Surprisingly, acidic regions were not restricted to hypoxic areas and overlapped with highly proliferative, invasive regions at the tumor–stroma interface, which were marked by increased expression of matrix metalloprotei-nases and degradation of the basement membrane. RNA-seq analysis of cells exposed to low pH conditions revealed a general rewiring of the transcriptome that involved RNA splicing and enriched for targets of RNA binding proteins with specificity for AU-rich motifs. Alternative splicing of Mena and CD44, which play important isoform-specific roles in metastasis and drug resistance, respectively, was sensitive to histone acetylation status. Strikingly, this program of alternative splicing was reversed in vitro and in vivo through neutralization experiments that mitigated acidic conditions. These findings highlight a previously underappreciated role for localized acidification of tumor microenvironment in the expression of an alternative splicing-dependent tumor invasion program.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Howard Hughes Medical Institute
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Center for Precision Cancer Medicine
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
10.1158/0008-5472.CAN-18-1604
https://doi.org/10.1158/0008-5472.CAN-18-1604
