Energetic regulation of coordinated leader–follower dynamics during collective invasion of breast cancer cells

Abstract

The ability of primary tumor cells to invade into adjacent tissues, followed by the formation of local or distant metastasis, is a lethal hallmark of cancer. Recently, locomoting clusters of tumor cells have been identified in numerous cancers and associated with increased invasiveness and metastatic potential. However, how the collective behaviors of cancer cells are coordinated and their contribution to cancer invasion remain unclear. Here we show that collective invasion of breast cancer cells is regulated by the energetic statuses of leader and follower cells. Using a combination of in vitro spheroid and ex vivo organoid invasion models, we found that cancer cells dynamically rearrange leader and follower positions during collective invasion. Cancer cells invade cooperatively in denser collagen matrices by accelerating leader–follower switching thus decreasing leader cell lifetime. Leader cells exhibit higher glucose uptake than follower cells. Moreover, their energy levels, as revealed by the intracellular ATP/ADP ratio, must exceed a threshold to invade. Forward invasion of the leader cell gradually depletes its available energy, eventually leading to leader–follower transition. Our computational model based on intracellular energy homeostasis successfully recapitulated the dependence of leader cell lifetime on collagen density. Experiments further supported model predictions that decreasing the cellular energy level by glucose starvation decreases leader cell lifetime whereas increasing the cellular energy level by AMP-activated kinase (AMPK) activation does the opposite. These findings highlight coordinated invasion and its metabolic regulation as potential therapeutic targets of cancer.

Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion

“…Differential energetic dynamics during invasion have been described in breast cancer, highlighting the need to further investigate metabolic heterogeneity during collective invasion in a variety of contexts 71 . We speculate that this difference could be due to molecular heterogeneity within and between cell types, the microenvironment, and various modes of migration, all of which could influence the metabolism of invading cells.…”

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

“…Cell migration is an energy consuming process. 50,51 However, hypoxia/HIF signaling typically occurs alongside nutrient deprivation and metabolic challenge, which may limit energy production required for cell migration. 52 Because hypoxia/HIF challenge induced conversion to amoeboid movement with efficient single-cell speeds in low-to mid-density 3D fibrillar collagen ( Supplementary Fig.…”

Leader cell activity and collective invasion by an autocrine nucleotide loop through connexin-43 hemichannels and ADORA1

“…suggested that the activity of leader cells was compromised. Leader cells are critical in initiating and maintaining collective invasion (Cheung et al, 2013;Zhang et al, 2019). To test whether leader cell function depends on Cx43, fluorescent mosaic spheroids of cells expressing nontargeting or Cx43 shRNA at equal ratio were allowed to invade.…”