Open AccessGALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment
Author(s) -
KiHoon Song,
Mi So Park,
Tulip Nandu,
Shrikanth S. Gadad,
Sang-Cheol Kim,
Miyoung Kim
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms13796
Subject(s) - metastasis , kras , lung , cancer research , breast cancer , lung cancer , tumor microenvironment , medicine , pi3k/akt/mtor pathway , biology , cancer , pathology , signal transduction , microbiology and biotechnology , colorectal cancer , tumor cells
Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies as well as their subsequent growth into overt metastases. Our results suggest that GALNT14 augments the self-renewal properties of breast cancer cells (BCCs). Furthermore, GALNT14 overcomes the inhibitory effect of lung-derived bone morphogenetic proteins (BMPs) on self-renewal and therefore facilitates metastasis initiation within the lung microenvironment. In addition, GALNT14 supports continuous growth of BCCs in the lung by not only inducing macrophage infiltration but also exploiting macrophage-derived fibroblast growth factors (FGFs). Finally, we identify KRAS-PI3K-c-JUN signalling as an upstream pathway that accounts for the elevated expression of GALNT14 in lung-metastatic BCCs. Collectively, our findings uncover an unprecedented role for GALNT14 in the pulmonary metastasis of breast cancer and elucidate the underlying molecular mechanisms.