Distal-less homeobox 5 gives rise to myofibroblastic carcinoma-associated fibroblasts to promote collective breast cancer invasion
- 1Department of Pathology and Oncology, Juntendo University Faculty of Medicine
Abstract
Tumor-promoting myofibroblastic carcinoma-associated fibroblasts (myCAFs) are induced by activation of transforming growth factor-{beta} signaling. However, the molecular basis of myCAF-specific transcriptional programs regulated by TGF-{beta} signaling remains poorly understood. Using a meta-analysis of single-cell RNA-seq data from 132 human breast tumor and non-tumor tissues, we show that myCAFs activate gene regulatory programs relevant to skeletal and cardiovascular development that are associated with poorer outcomes in breast cancer patients. Of note, distal-less homeobox 5 (DLX5), a master transcription factor for skeletal development, is activated in human breast myCAFs at both epigenetic and transcriptional levels. DLX5 expression is also initiated by TGF-{beta}1 treatment in human mammary fibroblasts. Immunoprecipitation and CUT&RUN assays using DLX5-expressing fibroblasts demonstrate that DLX5 interacts with Smad2/3/4 proteins, enabling their cooperative occupancy at shared genomic binding sites of target genes, thereby promoting canonical TGF-{beta} signaling and the myCAF state. DLX5-primed myCAFs also enhance paracrine TGF-{beta} signaling and neuropilin-2 expression to promote collective tumor invasion. Our findings indicate that DLX5 induces myCAF formation and promotes breast tumor progression in collaboration with canonical TGF-{beta} signaling.
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BibTeX
@misc{mezawa2026distalless,
title = {{Distal-less homeobox 5 gives rise to myofibroblastic carcinoma-associated fibroblasts to promote collective breast cancer invasion}},
author = {Y. Mezawa and K. Kumegawa and K. Morita and L. Yang and K. Hirakuri and K. Yamashita and T. Shirakihara and R. Sasaki and H. Onagi and G. Kutomi and R. Maruyama and A. Orimo},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.30.745418},
url = {https://www.biorxiv.org/content/10.64898/2026.08.30.745418v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Distal-less homeobox 5 gives rise to myofibroblastic carcinoma-associated fibroblasts to promote collective breast cancer invasion
AU - Y. Mezawa
AU - K. Kumegawa
AU - K. Morita
AU - L. Yang
AU - K. Hirakuri
AU - K. Yamashita
AU - T. Shirakihara
AU - R. Sasaki
AU - H. Onagi
AU - G. Kutomi
AU - R. Maruyama
AU - A. Orimo
PY - 2026
DA - 2026/08/30
PB - bioRxiv
DO - 10.64898/2026.08.30.745418
UR - https://www.biorxiv.org/content/10.64898/2026.08.30.745418v1
AB - Tumor-promoting myofibroblastic carcinoma-associated fibroblasts (myCAFs) are induced by activation of transforming growth factor-{beta} signaling. However, the molecular basis of myCAF-specific transcriptional programs regulated by TGF-{beta} signaling remains poorly understood. Using a meta-analysis of single-cell RNA-seq data from 132 human breast tumor and non-tumor tissues, we show that myCAFs activate gene regulatory programs relevant to skeletal and cardiovascular development that are associated with poorer outcomes in breast cancer patients. Of note, distal-less homeobox 5 (DLX5), a master transcription factor for skeletal development, is activated in human breast myCAFs at both epigenetic and transcriptional levels. DLX5 expression is also initiated by TGF-{beta}1 treatment in human mammary fibroblasts. Immunoprecipitation and CUT&RUN assays using DLX5-expressing fibroblasts demonstrate that DLX5 interacts with Smad2/3/4 proteins, enabling their cooperative occupancy at shared genomic binding sites of target genes, thereby promoting canonical TGF-{beta} signaling and the myCAF state. DLX5-primed myCAFs also enhance paracrine TGF-{beta} signaling and neuropilin-2 expression to promote collective tumor invasion. Our findings indicate that DLX5 induces myCAF formation and promotes breast tumor progression in collaboration with canonical TGF-{beta} signaling.
ER -