New Insights Into Breast Cancer Progression and Metastasis

Metastatic behaviour varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking, but could underlie the development of novel therapies. We have shown distinct phenotypes of metastatic tumor cells compared to primary tumor cells in triple negative breast cancer. While micro-metastases have a mesenchymal /stem cell-like phenotype, the actively proliferating macro-metastases are more differentiated, yet still distinct from primary tumors. The importance of the tumor microenvironment in controlling tumor progression and metastasis. The interplay between the primary breast cancer and innate immune response that it regulates, together control metastatic progression. In poorly metastatic tumors, the primary tumor recruits immune effector monocytes, which then act in cooperation with tumoricidal neutrophils to target disseminated tumor cells, preventing metastatic outgrowth. In metastatic tumors, the altered metastatic niche regulated by the primary tumor and a different phenotype of innate immune cells foster metastatic growth. These findings could underlie the development of novel immunotherapeutic target molecules.

Casbon, A.-J., D. Reynaud, C. Park, E. Khuc, D. D. Gan, K. Schepers, E. Passegué & Z. Werb (2015). Tumors reprogram early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. U.S.A. 112:E566-E575.

Lawson, D. A., N. Bhakta, K. Kessenbrock, K. Prummel, Y. Yu, K. Takai, A. Zhou, H. Eyob, S. Balakrishnan, C.-Y. Wang, P. Yaswen, A. Goga & Z. Werb (2015). Single-cell analysis reveals a stem cell program in early human metastatic breast cancer cells. Nature. 526, 131-135.

Devignes, C.-S., Y. Aslan, A. Brenot, A. Devillers, K. Schepers, S. Fabre, J. Chou, A.-J. Casbon, Z. Werb* & S. Provot* (2018). HIF signalling in osteoprogenitor cells promotes breast cancer growth and metastasis. Proc. Natl. Acad. Sci USA. 115: E992-E1001.

Takai, K., A. Drain, D. A. Lawson, L. E. Littlepage, M. Karpuj, K. Kessenbrock, A. Le, K. Inoue, V. M. Weaver & Z. Werb (2018). Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive, basal-like breast cancers. Genes Dev. 32:244-257.].

Nguyen, Q.H., N. Pervolarakis, K. Blake, D. Ma, R. T. Davis, N. James, A. T. Phung, E. Willey, R. Kumar, E. Jabart, I. Driver, J. Rock, A. Goga, S, Khan, D. A. Lawson, Z. Werb* & K. Kessenbrock* (2018). Profiling human breast epithelial cells using single cell RNA sequencing identifies cell diversity. Nat. Commun. 9:2028. doi: 10.1038/s41467-018-04334-1.