TGF-β1-mediated intercellular signaling fuels cooperative cellular invasion
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.
Authors
- Pritha Bagchi (ORCID: https://orcid.org/0000-0001-7229-9476)
- Gregory K. Tharp (ORCID: https://orcid.org/0000-0003-3075-755X)
- Isaac E. Robinson (ORCID: https://orcid.org/0000-0002-6773-6755)
- Paula M. Vertino (ORCID: https://orcid.org/0000-0001-6165-2019)
- Janna K. Mouw (ORCID: https://orcid.org/0000-0002-9846-8466)
- Sergei Bombin (ORCID: https://orcid.org/0000-0002-8333-932X)
- Emily R. Summerbell (ORCID: https://orcid.org/0000-0002-1336-1433)
- Christina M. Knippler (ORCID: https://orcid.org/0000-0003-3947-1830)
- Tala O. Khatib (ORCID: https://orcid.org/0000-0003-3052-8474)
- Jeanne Kowalski-Muegge
- Laura Marcus (ORCID: https://orcid.org/0000-0002-2316-0715)
- Adam I. Marcus (ORCID: https://orcid.org/0000-0003-0484-3569)
- Brian Pedro (ORCID: https://orcid.org/0000-0003-1898-3458)
- Sarah Webster (ORCID: https://orcid.org/0000-0002-9716-3249)
- Homa Ghalei (ORCID: https://orcid.org/0000-0003-0168-4654)
- H. Richard Johnston (ORCID: https://orcid.org/0000-0001-5668-1093)
- Veronika Y Matsuk
Institutions
- Johns Hopkins University (US)
- Emory University (US)
- Johns Hopkins Medicine (US)
- University of Rochester (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115315
- Citations
- 5
- Primary Topic
- TGF-β signaling in diseases
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Georgia Clinical and Translational Science Alliance
- National Cancer Institute