Clonal cooperation through soluble metabolite exchange facilitates metastatic outgrowth by modulating Allee effect

Tumours feature substantial heterogeneity of phenotypically distinct lineages. Although intra-clonal interactions between co-existing lineages is emerging as major contributor shaping tumor evolution, the extent and nature of interactions remain largely unknown. Here, we show that Allee effect, i.e., growth dependency on population size, is pervasive, and that intra-clonal soluble metabolite exchange alleviates the Allee thresholds to growth. Additionally, we find clear evidence for cooperative ecological interactions between lineages in that all clones are alleviated by reconditioned medium from the whole population; pairwise combinations of clones typically show cooperative interactions, as do polyclonal combinations. In mouse xenograft models, polyclonal metastasis formed from groups of interacting clones displayed enhanced metastatic outgrowth highlighting the physiological role of metabolic cooperation in vivo. Our results bring forward intra-tumor metabolite exchange as a modulator of tumor ecology and metastasis. RNA-seq, 2 conditions (A and C), Condition A 6 clones (03CR, 10CR, 13CR, 22CR, 35CR, and 45CR), Condition C 3 clones (22CR, 35CR, and 45CR), 3 replicates (R1, R2, R3).