Targeting metastatic cancer

Abstract

Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.

Fig. 1 |. Steps, biological functions and cancer cell vulnerabilities in the metastasis cascade.

Local surgery or radiation and systemic approaches including chemotherapy, targeted therapy and immunotherapy are currently the mainstay of metastasis prevention and treatment and are frequently effective at reducing metastatic tumor mass. However, these treatments do not specifically target the cryptic phase of metastasis or regenerative progenitors that persist following therapeutic debulking of macrometastatic disease. Cancer cells disseminating from a primary tumor via the blood or lymphatic system require specific functions (as listed under each boldface step) to adapt to a number of stresses in order to invade vessels, survive the loss of niche factors from the originating organ and survive in the circulation. On reaching distant organs (gray area), cancer cells enter and exit proliferative dormancy, evade immunity and acquire mitogenic signals by co-opting the stroma of the distant organs. The majority of cancer cells leaving a primary tumor are unable to survive these stresses and are cleared. Cancer cells that survive and retain the ability to regenerate the tumor during the cryptic phase of metastasis are called metastasis-initiating cells (MICs). MICs launch overt metastatic growth in distant organs, develop along tissue-regenerative trajectories and deploy organ-specific stromal co-option functions. Clinically overt macrometastases may be effectively debulked by classic therapies, but resistance and relapse are driven by the plasticity and persistence of MIC states within macrometastases. ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; MET, mesenchymal-epithelial transition.

Fig. 2 |. Model of metastasis subverting normal regenerative processes.

In normal epithelia, stem cells continuously generate differentiated progeny and maintain tissue homeostasis. Upon injury, quiescent progenitors emerge and give rise to proliferative daughter cells, which restore the epithelial barrier and lead to the regeneration of a homeostatic epithelium. Metastasis co-opts these regenerative processes. Oncogenic mutations in homeostatic stem cells generate primary tumor-initiating cells (CSCs). During tumor progression, cancer cells emerge that have a distinct regenerative progenitor phenotype. These cells can invade, disseminate and enter reversible quiescence to seed distant organs and eventually regrow a tumor, thus acting as MICs. Under appropriate environmental cues, these cells can regenerate heterogeneous tumors that recapitulate the developmental trajectories of the originating organ. Phenotypic plasticity (two-headed arrows) is prominent throughout these normal and tumorigenic regenerative processes.

Fig. 3 |. Classic and new opportunities for the treatment of metastatic cancer.

Targeting cancer cells with chemotherapy and targeted therapies is a mainstay of metastasis prevention and treatment. However, the recent success of ICI therapy demonstrates the value of targeting specific components of the tumor stroma (T cells) to treat metastasis. Leveraging recent insights into the regenerative origins, phenotypic plasticity, immune evasion and organ-specific colonization strategies of MICs could yield more potent approaches to prevent metastasis by targeting its cryptic phase during dormancy and micrometastasis and to augment the efficacy of ICI and other therapies by more effective elimination of drug-resistant macrometastatic disease. CAFs, cancer-associated fibroblasts; T_reg, regulatory T cells; NK, natural killer cells; TGF-β, transforming growth factor-β.