Abstract IA25: Metastasis pathways

The mechanisms that turn disseminated tumour cells (DTCs) into metastasis-initiating seeds are largely unknown. We recently identified molecular sensors and stromal factors that amplify cell survival and stem cell pathways in DTCs from breast, lung, and renal cancers. These mechanisms prime tumor cells for metastasis in animal models and are associated with relapse in patients. For example, SRC primes triple-negative (TN) breast cancer DTCs for a robust response of the PI3K-Akt pathway to CXCL12 and IGF1 in the bone marrow. The leukocyte-tethering receptor VCAM-1 primes TN DTCs for PI3K-Akt activation in the lungs. For stem cell fitness, the extracellular matrix protein tenascin-C (TNC) forms micrometastatic niches that amplify WNT and NOTCH signaling in TN breast cancer cells. A CXCL1-S100A8 paracrine loop protects DTCs from the stresses of metastasis and chemotherapy, suggesting a link for the clinically coupled phenomena of relapse and chemoresistance. Though encouraging, this progress has only accentuated an old puzzle: How do organ-specific metastatic traits emerge in primary tumors? We identified a role of the breast tumor stroma in selecting cancer cells in TN breast cancers that are primed for metastasis to bone. Cancer-associated fibroblasts (CAFs) in TN breast tumors skew heterogeneous cancer cell populations towards a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. Coupled with processes of tumour self-seeding, whereby DTCs may recirculate, reseed and expand in their tumors of origin, the process of metastatic seed pre-selection may further sway the organotropic metastatic traits of tumors. We conclude that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumour and its distant metastases.

In related studies we identified mediators of brain metastasis of lung adenocarcinoma and breast cancer.

Citation Format: Joan Massagué. Metastasis pathways. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA25.