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Acidification of Tumor at Stromal Boundaries Drives Transcriptome Alterations Associated with Aggressive Phenotypes | 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 metalloproteinases 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.
acidification  tumor_stromal_boundary  mena  splicing  PyMT  231_cells  low_pH  MMP14  CD44 
may 2019 by Segalllab
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4B) In 2011, Japanese group showed mutations actually most common class of mutation in MDS. By then I'd…
splicing  from twitter_favs
april 2018 by maverickny
TCGASpliceSeq a compendium of alternative mRNA splicing in cancer
site for downloading splice isoform fractions for a single gene from the TCGA
splicing  tcga 
february 2018 by Segalllab
An atlas of alternative splicing profiles and functional associations reveals new regulatory programs and genes that simultaneously express multiple major isoforms
An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms
splicing  resource  database  RNA  Databases 
october 2017 by ioannis
Oncogene - The ErbB2[Delta]Ex16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment
ErbB2 splice variant seems to naturally be present at 2-10% of total ErbB2, thus is high in ErbB2 overexpressing lines. Appears to enhance SMAD/HIF signaling and more rapid induction of mammary tumors. Note the increased stromal trichrome staining image!
ErbB2  splicing  MMTV_Neu  mammary_tumors 
march 2017 by Segalllab

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