Regulation of Collective Metastasis by Nanolumenal Signaling
This week we profile a recent publication in Cell from
Dr. Kevin Cheung and Emma Wrenn (pictured) at Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
Our lab studies the biology of tumor cell clusters and their role in metastasis. Recent research has shown that when tumor cells disseminate as multicellular clusters they have far greater potential to form new metastases. However, the exact mechanisms underlying this high metastatic potency are still largely unknown. We use organoid and mouse models to study the fundamental biology of how cells communicate and cooperate with one another to invade, disseminate, and colonize distant tissues collectively. Our ultimate goal is to translate these findings into better treatments for breast cancer.
What is the significance of the findings in this publication?
We and other groups have shown that tumor cell clusters have up to 500-fold higher metastatic outgrowth than single cells, but the biology behind this massive difference has remained mysterious.
In this study we identified a growth factor, epigen, that is highly upregulated in tumor cell clusters. When this growth factor is knocked down in tumor cell clusters, metastatic outgrowth in the lungs was reduced by over 94%. These data show that epigen is a signal for metastatic outgrowth of tumor cell clusters, and suggest that it could be used as a therapeutic target against cluster-based metastasis.
Surprisingly, we found that epigen promotes growth by being concentrated within intercellular cavities, which we have termed “nanolumina”. These nanolumina are sealed by cell-cell junctions with restricted permeability, protecting them from the external environment and preserving high concentrations of epigen which is shared amongst cells in the cluster. We observed these sealed nanolumina across a number of different mouse models, human cell lines, and human patient samples, supporting the human disease relevance of this finding.
Our study indicates that the 3D organization of cells in a cluster generates emergent signaling properties important for metastasis. Additionally, the restricted permeability of nanolumenal junctions suggests that therapies which can open nanolumina, freeing their contents and possibly improving drug access, could be beneficial to patients.
What are the next steps for this research?
Now that we understand this nanolumenal signaling mechanism, we can try to develop therapeutics to interrupt it and reduce metastatic burden in patients. Part of this research will involve identifying subsets of patients, or even other cancer types, that contain nanolumina and depend on this type of collective signaling for growth or survival. Moreover, we are interested to see what other functions nanolumina may serve in addition to epigen concentration, both in cancer and normal development. As part of this project, we are developing proteomic techniques to assess the contents of nanolumina in an unbiased manner to better understand their signaling functions.
This work was funded by:
Grants from the Department of Defense Breast Cancer Research Program (BCRP; W81XWH-18–1–0098), the NIH/NCI (R37CA234488), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Breast Cancer Research Foundation (BCRF-18-035), the V Foundation (V Foundation Scholar Award), the Phi Beta Psi Sorority, Seattle Translational Tumor Research, and the Shared Resources of the FHCRC/UW Cancer Consortium (P30 CA015704).