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Twist1 induces distinct cell states depending on TGFBR1-activation

Titel Pressemitteilung:

Designierter Wirkstoff macht Tumorzellen aggressiver

Breast cancer progression – The devil is in the detail

Oct 2016 ISF
Dr. Christina Scheel PDF
PR 2016-04-01
Core statement:

Basic helix-loop-helix transcription factor Twist1 is a master regulator of
Epithelial-Mesenchymal Transition (EMT), a cellular program implicated in different
stages of development as well as metastatic dissemination of carcinomas. Here, we
show that Twist1 requires TGF-beta type-I receptor (TGFBR1)-activation to bind an
enhancer region of downstream effector ZEB1, thereby inducing ZEB1 transcription
and EMT. When TGFBR1-phosphorylation is inhibited, Twist1 generates a distinct cell
state characterized by collective invasion, simultaneous proliferation and expression
of endothelial markers. By contrast, TGFBR1-activation directs Twist1 to induce stable
mesenchymal transdifferentiation through EMT, thereby generating cells that display
single-cell invasion, but lose their proliferative capacity. In conclusion, preventing
Twist1-induced EMT by inhibiting TGFβ-signaling does not generally block acquisition
of invasion, but switches mode from single-cell/non-proliferative to collective/
proliferative. Together, these data reveal that transient Twist1-activation induces
distinct cell states depending on signaling context and caution against the use of
TGFβ-inhibitors as a therapeutic strategy to target invasiveness.

Core statement Pressemitteilung:

Researchers at Helmholtz Zentrum München describe how breast cancer cells challenged with a small-molecule inhibitor targeting specific invasive properties switch to an alternative mode-of-action, rendering them even more aggressive. The results may impair future therapeutic approaches in the TGF-beta pathway and are published in the journal ‘Oncotarget’.

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