Tumor cell metastasis

Project leaders: Dr. Boris Strilic
PhD Students: Kenneth Roquid, Adriana Vucetic

Metastasis, the spreading of tumor cells mainly through the vascular system, accounts for the majority of cancer-associated deaths. However, the complex processes underlying tumor cell dissemination and growth of metastasis have remained poorly understood. Increasing evidence indicates that the microenvironment of the metastatic site plays a critical role in determining the progression of metastatic cancer. This includes the pre-metastatic niche which forms under the influence of ill-defined factors released from the primary tumor before tumor cells reach their metastatic sites. After tumor cells have arrived at places of metastasis, a local microenvironment forms and influences the fate of tumor cells which may die, grow or enter into a state of dormancy. Dormancy of metastasized tumor cells requires still poorly-understood conditions which support survival, suppress proliferation and may even provide resistance to therapeutic agents.

In the past, we have focused on the interaction of tumor cells with endothelial cells in the context of extravasation at metastatic sites (Schumacher et al., 2013; Strilic and Offermanns, 2017), and we recently identified mechanisms mediating tumor cell extravasation and efficient metastasis formation (Strilic et al., 2016). In the future, we plan to (1) further characterize mechanisms underlying tumor cell intravasation and extravasation, (2) characterize the pre-metastatic niche with a focus on the microvasculature and its role in promoting tumor cell metastasis and (3) identify local and systemic mechanisms which regulate tumor cell dormancy.

Literature

• Nakayama A, Roquid KA, Iring A, Strilic B, Günther S, Chen M, Weinstein LS, Offermanns S. (2023) Suppression of CCL2 angiocrine function by adrenomedullin promotes tumor growth. J Exp Med. 220, e20211628.
• Yang L, Joseph S, Sun T, Hoffmann J, Thevissen S, Offermanns S, Strilic B. (2019) TAK1 regulates endothelial cell necroptosis and tumor metastasis. Cell Death Differ. 26: 1987-1997
• Strilic B, Offermanns S. (2017) Intravascular Survival and Extravasation of Tumor Cells. Cancer Cell 32: 282-293
• Strilic B, Yang L, Albarrán-Juárez J, Wachsmuth L, Han K, Müller UC, Pasparakis M, Offermanns S (2016). Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536: 215-218
• Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S (2013). Platelet-derived nucleoides promote tumor-cell transendothelial migration and metastasis via P2Y₂ receptor. Cancer Cell 24: 130-137