Plasticity of cancer invasion and energy metabolism

Abstract

Energy deprivation is a frequent adverse event in tumors that is caused by mutations, malperfusion, hypoxia, and nutrition deficit. The resulting bioenergetic stress leads to signaling and metabolic adaptation responses in tumor cells, secures survival, and adjusts migration activity. The kinetic responses of cancer cells to energy deficit were recently identified, including a switch of invasive cancer cells to energy-conservative amoeboid migration and an enhanced capability for distant metastasis. We review the energy programs employed by different cancer invasion modes including collective, mesenchymal, and amoeboid migration, as well as their interconversion in response to energy deprivation, and we discuss the consequences for metastatic escape. Understanding the energy requirements of amoeboid and other dissemination strategies offers rationales for improving therapeutic targeting of metastatic cancer progression.

Keywords: amoeboid migration; cellular bioenergetics; metabolic stress; migration plasticity.

Figure 1.. Energy consuming processes during migration.

Overview (top panel) and individual ATP-consuming steps involved in cell movement (bottom panels, A-F). (A) Actin-ATP monomers polymerize to filaments. Filament dynamics are controlled by actin-binding proteins, including cofilin, under the control of LIMK and phosphatases, under the control by Rac1. Rac 1 further controls PAK1- Arp2/3 engagement for filament branching. NM II mediates actin filaments contraction, under the control of MRLC phosphorylation regulated by MLCK and MLCP controlled by Rac1 and RhoA, respectively. (B) ATP consumption is involved in cadherin adaptor molecules regulation via phosphorylation as p120 is under Src kinases activity. In response to external forces, E-cadherin stimulates AMPK signaling. AMPK stimulates increased glucose uptake and its conversion into ATP. AMPK further acts on kinases (Abl) to phosphorylate vinculin and the RhoA–ROCK-myosin II axis. (C) Integrins activity, clustering and turn-over require energy as they are regulated by cycles of phosphorylation and dephosphorylation of their cytoplasmatic tail and adaptor proteins. The examples show paxillin phosphorylation by FAK and Src kinases and filamin A controlled by Rac1-PAK1 axis. (D) ATP is engaged in MRCK activity and regulation by the Rho GTPase Cdc42, which leads to myosin contractility around the nucleus. ATP is further required for LINC complex activity and actin cable dynamics. For example, Rac1 interacts with Nesprin-2 to connect the LINC complex to actin. Src-mediated phosphorylation of Lamin A causes lamin A disassembly from the inner nuclear lamina. (E) ATP-dependent phosphorylation and regulation of ion channel pumping into the cytoplasm and aquaporin activity. For example, AQP-2 is phosphorylated by PKA, and activated by cAMP. (F) ATP-consuming steps during ECM degradation, including kinesin and dynein-mediated vesicle transport of proteases, endo/exocytic protease transport, autocatalytic activation of the zymogen; zymogen cleavage by activating protease. MT1-MMP activity can further be regulated through LIMK-mediated phosphorylation of the cytoplasmic tail. Created with BioRender.com

Fig. 2.. Interdependence of energy consumption and migration strategy.

Collective migration depends on strong cell-cell adhesion, Rac1-mediated actin dynamics, Rho-A mediated contractility, integrin-mediated ECM adhesion and deformation together with pericellular proteolysis. Because of its molecular and mechanical complexity, collective migration is energetically costly, particularly for the leader cells that must overcome substrate resistance. Collective-to-mesenchymal (CMT) single-cell transition is mediated by the downregulation of intercellular adhesions. Losing cell-cell junctions allows mesenchymal single cells to save some energy, even though their elongated morphology still requires actin activity at the leading edge, cytoskeletal contractility, ECM-adhesion, and proteolysis. Mesenchymal-to-amoeboid transition (MAT) results from lowering adhesion to the substrate and pericellular proteolysis. The pseudopodal amoeboid mode retains actin-rich protrusions while the blebbing mode completely relies on Rho-mediated actomyosin contractility. By lowering most of the ATP-consuming steps of motility, the amoeboid mode seems to minimize the energy demands of migration. The lower panel shows the hypothetical coupling of migration modes and metabolic reprogramming. Created with BioRender.com

Fig. 3.. Amoeboid cancer cell migration – an “eco-mode”.

Hypoxic stress triggers the collective-to-amoeboid transition. This switch in migration mode relies on HIF-1a-mediated activation of calpain-2, a protease that cleaves Talin-1 and therefore decreases b1-integrin activity. This weakening of interactions with the ECM causes cell rounding and the formation of polarized membrane blebs. This transition to an amoeboid and more cost-effective type of migration might secure cell evasion from challenging microenvironments. Created with BioRender.com