PT  - JOURNAL ARTICLE
AU  - Jie Dong
AU  - Cedric Darini
AU  - Farhia Kabeer
AU  - Sarah Dendievel
AU  - Junxia Min
AU  - Dolores Hambardzumyan
AU  - Louis Gaboury
AU  - Tom Lenaerts
AU  - Guillaume Darrasse-Jèze
AU  - Yi Li
AU  - Katrina Podsypanina
TI  - An evolving cancer instigates clonally unrelated neighboring cells to form distant metastases
AID  - 10.1101/085423
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 085423
4099  - http://biorxiv.org/content/early/2016/11/03/085423.short
4100  - http://biorxiv.org/content/early/2016/11/03/085423.full
AB  - Based on the clonal evolution theory of cancer formation, a single cell within a tissue gains a cancer-driving mutation and thus a growth advantage. From this expanded cellular mass, another cell gains a new mutation allowing this newly mutated cell to gain new competitive advantage and to expand in number (thus clonal expansion). Another clone then emerges. Eventually all required mutations are gained, and a cancer forms. Consequently, while a primary lesion may harbor divergent subclones, all the subclones within the primary cancer as well as all metastatic growths in secondary organs share at least the very first oncogenic mutation that initiates the primary cancer. However, by tracking genetically marked mammary epithelial cells that suffered the initiating oncogenic mutation—and their neighboring mammary cells that did not-in several mouse models of human breast cancer, we found that genetically unrelated mammary epithelial cells can be colluded by neighboring mutated cells to disseminate, and that they can even undergo de novo tumorigenic transformation and form distant metastases. Therefore, clonally unrelated epithelial cells may contribute to cancer progression and to the heterogeneity of the systemic disease. The non-linear cancer spread has important implications in cancer prevention, treatment, and therapeutic resistance.