Metastasis prevention by targeting the dormant niche

Abstract

Despite considerable advancements that shattered previously held dogmas about the metastatic cascade, evolution of therapies to treat metastatic disease has not kept up. In this Opinion article, I argue that rather than waiting for metastases to emerge before initiating treatment, it would be more effective to target metastatic seeds before they sprout. Specifically, I advocate directing therapies towards the niches that harbor dormant disseminated tumor cells in order to render them susceptible to cytotoxic agents. Treatment sensitization achieved by disrupting reservoirs of leukemic stem cells and latent HIV argues that this approach, though unconventional, could succeed in improving patient survival by delaying or even preventing metastasis.

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

“…In addition, IFN-β did not induce B16 and A375 TRCs to undergo senesence, as evaluated by β-gal activity ( Figure 2E). Dormant tumor cells may also decrease their response to xenobiotics, including chemotherapeutic drugs (31,32). We found that IFN-β-treated B16 and A375 TRCs were more resistant to methatrexate and paclitaxol than control TRCs ( Figure 2F).…”

Distinctive properties of metastasis-initiating cells

“…Dormant DTCs have been defined with three main features: growth arrest, survival, and therapy resistance (Ghajar 2015). Furthermore, their entry into dormancy and reactivation not only is triggered by intrinsic programs but is also dependent on specialized microenvironmental niches, extrinsic signals, and immune effects (Giancotti 2013;Quail and Joyce 2013;Sosa et al 2014).…”

“…However, dormant cancer cells can also escape existing cancer treatments because of their quiescent status or niche protection (Braun et al 2000;Naumov et al 2003). Therefore, dormancy-specific treatment strategies should be designed to target the dormant cells (Sosa et al 2014;Ghajar 2015). Furthermore, other MIC-associated features, such as metabolic reprogramming and activation of survival pathways, are additional candidates for developing new treatment options (Holohan et al 2013;Loo et al 2015).…”

Bringing together the organoid field: from early beginnings to the road ahead

“…Ghajar showed how plating on a bed of human microvasculature in 3D culture induced dormant behavior in tumor cells by protecting against their death. He made the case that this model has significant implications for understanding dormancy in cancer and, importantly, how these cells are later re-awakened (Ghajar, 2015;Ghajar et al, 2013).…”