IBMS BoneKEy | BoneKEy Watch
Gao et al. Pathway discovered that reactivates dormant metastatic breast cancer
DOI:10.1038/bonekey.2016.92
Mouse genetic screens developed to study the pathways involved in breast cancer reactivation were used to identify TM4SF1, an atypical tetraspanin as a major factor in the reactivation of dormant metastatic breast cancer cells in several organs, including bone.
The mechanism by which TM4SF1 reactivates cancer cells seems to reply on coupling the collagen receptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2. This then activates PKCa, which, in turn phosphorylates and activates JAK2 and subsequently STAT3.
This is a non-canonical signaling mechanism that induces SOX2 and NANOG expression and encourages dormant breast cancer cells to become cancer stem cells, enabling them to interact with collagen I, a component of the interstitial matrix in many different organs. This newly discovered signaling pathway is therefore able to drive metastatic reactivation of breast cancer in the brain, lung and bone.
The authors suggest that using currently available JAK2 kinase inhibitors or other therapeutic agents to disrupt the association of DDR1 with TM4SF1 could help prevent breast cancer metastasis when used in combination with chemotherapy and oncogene-targeted therapy.
Editor’s comment: The observation that TM4SF1 induces noncanonical DDR1 signaling to reactivate disseminated breast cancer cells and promote metastasis in distant organs (brain, lung and bone) is of the utmost importance, as it opens novel therapeutic approaches that could eradicate residual disease by targeting the association of TM4SF1 with DDR1.
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