Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts
- 1Institute for Research in Immunology and Cancer, Université de Montréal
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, in part due to a dense and highly plastic tumor microenvironment dominated by cancer-associated fibroblasts (CAFs). In previous work, we identified a CAF population expressing a neural-associated NES+SOX4+NOTCH1+ program that increased with disease progression. The signals driving this state and the mechanisms regulating it remained unclear. Here, we investigated how tumor-derived signals activate this program and whether it represents a stable fibroblast identity or a reversible state. Using spatial transcriptomic data spanning normal pancreas to invasive carcinoma, we identified EGF, FGF2 and BDNF as candidate tumor-to-fibroblast signals associated with disease progression. Functional experiments in patient-derived CAFs and human fibroblast cell lines showed that EGF and FGF2 are sufficient to induce the NES+SOX4+NOTCH1+ program. Growth factor withdrawal reversed the NES+SOX4+NOTCH1+ program at both the protein and transcriptional levels, indicating that this state is dynamic and environment dependent. Single-cell transcriptomic analysis further revealed a multi-phase response involving early loss of fibroblast-associated features, transient activation of neural-associated genes, and a later stress-associated state. Regulatory analyses identified ETS-family transcription factors as key regulators of the program, while phosphoproteomic profiling and inhibitor studies showed that MAPK/ERK signaling plays a central role in its transcriptional activation. Finally, pan-cancer single-cell analysis showed that this state is enriched in CAFs and increases from normal to tumor tissue across multiple cancer types. Together, these findings define a reversible, growth factor-driven CAF program and identify signaling mechanisms that may provide opportunities to selectively modulate tumor-supportive fibroblast states.
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BibTeX
@misc{ibanezrios2026tumourstroma,
title = {{Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts}},
author = {M. I. Ibanez-Rios and M. Batardiere and E. Dianati and G. Serwe and S. Kanagasingam and A. Archambault-Marsan and P. Thibault and M. Therrien and V. Q.-H. Trinh and D. J. Knapp},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757165},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757165v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts
AU - M. I. Ibanez-Rios
AU - M. Batardiere
AU - E. Dianati
AU - G. Serwe
AU - S. Kanagasingam
AU - A. Archambault-Marsan
AU - P. Thibault
AU - M. Therrien
AU - V. Q.-H. Trinh
AU - D. J. Knapp
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757165
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757165v1
AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, in part due to a dense and highly plastic tumor microenvironment dominated by cancer-associated fibroblasts (CAFs). In previous work, we identified a CAF population expressing a neural-associated NES+SOX4+NOTCH1+ program that increased with disease progression. The signals driving this state and the mechanisms regulating it remained unclear. Here, we investigated how tumor-derived signals activate this program and whether it represents a stable fibroblast identity or a reversible state. Using spatial transcriptomic data spanning normal pancreas to invasive carcinoma, we identified EGF, FGF2 and BDNF as candidate tumor-to-fibroblast signals associated with disease progression. Functional experiments in patient-derived CAFs and human fibroblast cell lines showed that EGF and FGF2 are sufficient to induce the NES+SOX4+NOTCH1+ program. Growth factor withdrawal reversed the NES+SOX4+NOTCH1+ program at both the protein and transcriptional levels, indicating that this state is dynamic and environment dependent. Single-cell transcriptomic analysis further revealed a multi-phase response involving early loss of fibroblast-associated features, transient activation of neural-associated genes, and a later stress-associated state. Regulatory analyses identified ETS-family transcription factors as key regulators of the program, while phosphoproteomic profiling and inhibitor studies showed that MAPK/ERK signaling plays a central role in its transcriptional activation. Finally, pan-cancer single-cell analysis showed that this state is enriched in CAFs and increases from normal to tumor tissue across multiple cancer types. Together, these findings define a reversible, growth factor-driven CAF program and identify signaling mechanisms that may provide opportunities to selectively modulate tumor-supportive fibroblast states.
ER -