Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5⁺ tumor stem cell lineage commitment upon Wnt depletion.

Authors

Marika Lassila, Fatemeh Seyednasrollah, Cinzia Bessone, Maritta Räisänen, Inkeri Vuori, Davide G Berta, Johanna Aspholm, Tatiana V Petrova, Lauri A Aaltonen, Kari Alitalo, Pauliina Kallio

Published in

Science advances. Volume 12. Issue 28. Pages eaeb8564. Jul 10, 2026. Epub Jul 10, 2026.

Abstract

Plasticity, the capability of tumor cells to go through phenotypic transitions, promotes colorectal cancer (CRC) progression and treatment resistance. Although plasticity is evident in advanced CRCs, little is known about plasticity in early-stage tumors and tumor stem cells. Here, we demonstrate that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1⁺ tumor stem cells. We furthermore analyzed progressive plasticity upon loss of the canonical wingless-related integration site (Wnt) effector Tcf7 or Lef1 in Apc mutant mice. Deletion of either gene led to emergence of new plastic tumor cell populations, failure of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) tumor stem cell differentiation into enterocyte-like cells, enhanced Myc pathway activation, and increased tumor cell proliferation and tumorigenesis. Together, we demonstrate that PCS is associated with early CRC development and identify multiple potentially druggable mechanisms activated during progressive tumor cell plasticity.

PMID:
42430492
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.

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