TGF-β1-mediated intercellular signaling fuels cooperative cellular invasion

Cell Rep. 2025 Feb 25;44(2):115315. doi: 10.1016/j.celrep.2025.115315. Epub 2025 Feb 15.

Abstract

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.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Communication*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Humans
  • Jagged-1 Protein / metabolism
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Neoplasm Invasiveness
  • Signal Transduction*
  • Transforming Growth Factor beta1* / metabolism

Substances

  • Transforming Growth Factor beta1
  • Jagged-1 Protein