Abstract IA13: Niches and pathways of latent and overt metastasis

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Abstract The signals and niches that allow disseminated tumor cells (DTCs) to stay viable as metastasis seeds are largely unknown. An understanding of these mechanisms is needed for the development of treatments to eradicate DTCs and prevent metastasis. We have identified molecular mechanisms that prime breast cancer DTCs for survival and stem cell fitness in distant organs. For survival, SRC primes DTCs for a robust PI3K-Akt response to CXCL12 and IGF1 in the bone marrow, and the leukocyte-tethering receptor VCAM-1 primes DTCs for PI3K-Akt activation by leukocyte contacts in the lungs. For stem cell fitness, the extracellular matrix protein tenascin-C (TNC) forms micrometastatic niches that promote WNT and NOTCH signaling. Additionally, a CXCL1-S100A8 paracrine loop protects DTCs from the stresses of metastasis and chemotherapy, providing a basis for these two clinically linked phenomena. In some cases, the pathways driving carcinoma formation additionally mediate metastasis. VHL inactivation leads to HIF signaling as a tumor-initiating event in clear cell renal carcinoma (ccRCC). However, VHL mutation status in ccRCC is not correlated with clinical outcome. We found that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis through CXCR4 and CYTIP. The strength of this activation is associated with poor clinical outcome. Thus, metastasis can be driven by an epigenetically expanded output of the tumor-initiating pathway as well as by events that are mechanistically uncoupled from the tumor-initiating pathway. In preclinical models, SRC kinase inhibitors, VCAM-1 blocking antibodies, and CXCL1 receptor inhibitors suppress metastasis and augment the efficacy of chemotherapy, providing new avenues for targeting DTCs in the adjuvant setting. Citation Format: Joan Massagué. Niches and pathways of latent and overt metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA13.