Intratumoral heterogeneity drives cancer progression and influences treatment outcomes. The mechanisms underlying how cellular subpopulations communicate and cooperate to impact progression remain largely unknown. Here, we use collective invasion as a model to deconstruct processes underlying non-small cell lung cancer subpopulation cooperation. We reveal that collectively invading packs consist of heterogeneously cycling and non-cycling subpopulations using distinct pathways. We demonstrate that the follower subpopulation secretes transforming growth factor beta one (TGF-β1) to stimulate divergent subpopulation responses-including proliferation, pack cohesion, and JAG1-dependent invasion-depending on cellular context. While isolated followers maintain proliferation in response to TGF-β1, isolated leaders enter a quiescence-like cellular state. In contrast, leaders within a heterogeneous population sustain proliferation to maintain subpopulation proportions. In vivo, both leader and follower subpopulations are necessary for macro-metastatic disease progression. Taken together, these findings highlight that intercellular communication preserves tumor cell heterogeneity and promotes collective behaviors such as invasion and tumor progression.
Keywords: CP: Cancer; cell cycle progression; collective invasion; heterogeneity; intercellular cooperation; tumor progression.
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