Abstract A155: The TGF-β/BMP signaling cascades induce opposing fates in breast cancer and medulloblastoma through chromatin and cell cycle modulation

Abstract

Abstract The transforming growth factor β (TGF-β) superfamily comprises more than 30 structurally-related proteins, including TGF-β1, TGF-β2, TGF-β3 and bone morphogenesis proteins (BMPs). TGF-β/BMP ligands bind to their respective kinase receptors culminating paradoxically in either tumor-promoting or suppressing outcomes. The former fate is attributed mainly to the induction of the epithelial-mesenchymal transition and microenvironmental remodeling by TGF-β/BMP, whereas the latter outcome is a consequence of various antiproliferative mechanisms. To gain a broader perspective, we studied the fates of different cancer models, including breast cancer and medulloblastoma, either challenged with TGF-β/BMP ligands or depleted of essential transcription factors. In 3D cultures, TGF-β stimulation enhances the genome-wide chromatin accessibility of normal-like and transformed breast epithelial models. Concomitantly, we observed a dramatic increase in accessible regions mapped to transcription start sites and, to less extent, at annotated enhancers. The corresponding transcriptome-wide analyses indicated positive modulation of DNA replication and repair associated with resistance to cyclin-dependent kinase inhibition in breast cancer organoids. Nevertheless, such TGF-β-induced remodeling was partly dependent on the activity of the transcription factor SOX4. Further implementation of whole transcriptome spatial profiling in medulloblastoma PDX tissues identified several cell cycle-related pathways and chromatin remodeling terms that negatively associate with activated BMP signaling. In this context, the stem cell capacity of medulloblastoma spheroids was significantly inhibited by BMP stimulation in vitro. Moreover, we uncovered a regulatory network that maintains the transcriptional activation of BMP receptor type I (ACVR1) through the LHX2 transcription factor that maintains an active chromatin landscape at the ACVR1 proximal promoter. The depletion of LHX2 resulted in reduced tumor formation capacity of medulloblastoma in vivo. Taken together, our extensive studies across multiple model systems suggest that the TGF-β superfamily remodels the chromatin state to alter the cell cycle progression and, subsequently, affect cancer stemness and cell fate. Citation Format: Mohamad Moustafa Ali, Yae Ohata, Carl-Henrik Heldin, Aristidis Moustakas. The TGF-β/BMP signaling cascades induce opposing fates in breast cancer and medulloblastoma through chromatin and cell cycle modulation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A155.