Metastasis

Abstract

Most cancer-associated deaths occur due to metastasis, yet our understanding of metastasis as an evolving, heterogeneous, systemic disease and of how to effectively treat it is still emerging. Metastasis requires the acquisition of a succession of traits to disseminate, variably enter and exit dormancy, and colonize distant organs. The success of these events is driven by clonal selection, the potential of metastatic cells to dynamically transition into distinct states, and their ability to co-opt the immune environment. Here, we review the main principles of metastasis and highlight emerging opportunities to develop more effective therapies for metastatic cancer.

Figure 1.. Stages of metastasis

Metastasis comprises three stages: dissemination, dormancy, and colonization, which can coexist and overlap in time. MICs arise from primary tumors and have acquired the ability to undergo invasive migration and then singly or collectively migrate and disseminate via the blood or lymphatics as CTCs. Most CTCs are cleared due to physical, biochemical, and immunological stressors. Trapped in capillary beds of distant organs, CTCs extravasate and migrate into organ parenchyma as DTCs to seed nascent metastasis. DTCs seed in organ-specific, perivascular niches. The majority are cleared by niche-specific or systemic immune defenses, but few MICs survive, entering reversible growth arrest and immune-evasive quiescence, acquire organ-specific growth adaptations, and co-opt their TME to evade immune surveillance. Environmental triggers lead MICs to exit dormancy and form clinically detectable macrometastases.

Figure 2.. Principles of metastasis

MICs acquire a set of functional abilities that enable them to disseminate, colonize, and survive multiple stressors in a hostile environment, summarized here as the principles of metastasis.

Figure 3.. Co-option of developmental and regenerative programs during metastasis

Metastatic cells redeploy developmental and regenerative programs of normal embryonic development and wound healing. (A) During homeostasis, tissue-specific stem cells continuously generate transit-amplifying progenitors and mature differentiated cells. Upon tissue injury, differentiated epithelial cells dedifferentiate to re-enter tissue fetal-like, damage-associated transient progenitor states that can differentiate into tissue stem cells and then diverse differentiated cells, restoring epithelial integrity. (B) Cell plasticity and fate become progressively restricted during embryonic development. Upon tissue injury, fate-restricted differentiated cells undergo transient increases in plasticity. Cancer cells co-opt programs employed by developmental and regenerative progenitors in adaptation to stresses during tumor progression, although whether cells in macrometastases remain highly plastic or become fate-restricted remains unclear. (C) Disseminated MICs adopt high-plasticity states. These include hybrid EMT states, damage-associated transient progenitor-like states or immune-evasive dormant states. During metastatic colonization, MICs can regenerate phenotypically heterogeneous macrometastatic tumors that can enter dormancy or initiate tumor growth, re-enter states similar to the primary tumor (elasticity), remain trapped in MIC-like states (deformability), or undergo lineage plasticity into new cell states not found in the primary tumor (transdifferentiation).

Figure 4.. The metastatic tumor microenvironment

The composition and co-option of the TME is essential for tumor growth and progression. Main components of the TME are components of the innate and adaptive immune system as well as stromal cells: tissue-resident and bone-marrow-derived macrophages, polarized into immunosuppressive TAMs, monocytes, myeloid-derived suppressor cells, T cells, NK cells, dendritic cells, blood and lymphatic vessels, cancer-associated fibroblasts, and components of the ECM. The environment of immune cells in the TME and expression of immune regulatory receptors becomes more immunosuppressed in metastatic tumors.

Figure 5.. Current and emerging therapeutic strategies for metastatic disease

(A) Metastatic disease is treated in three contexts: Micrometastatic disease is suspected in the (neo-)adjuvant therapeutic setting when metastatic disease cannot be detected by standard imaging and screening technologies. Although multi-organ macrometastasis is largely incurable, selective local therapy of oligometastatic disease can prolong life and sometimes be curative for several cancers. Multi-organ metastatic disease is generally treated with systemic therapy, including chemotherapy, targeted therapy (e.g., small-molecule inhibitors, antibodies, or antibody-drug-conjugates), and immunotherapy. (B) Opportunities for therapeutic modalities that target cancer cells or their TME to maximize elimination of metastatic cells are highlighted. In micrometastasis, MICs are in dynamic equilibrium with immune surveillance. Proliferating cells are frequently eliminated by tissue-resident or circulating immune cells, whereas dormant cells evade immune destruction. In oligometastasis, small tumors are infiltrated by TME resident cells and recruited immune cells. In multi-organ metastasis, the TME becomes increasingly immunosuppressive, expelling tumor-reactive immune cells or co-opting them into immunosuppressive states.