# NONO links circadian rhythm disruption and enhanced tumor-fibroblast crosstalk in right-sided colorectal cancer

## TL;DR

This study reveals how circadian rhythm disruption in right-sided colorectal cancer is linked to tumor-fibroblast interactions through a protein called NONO.

## Contribution

The study identifies NONO as a key regulator linking circadian disruption to tumor-fibroblast communication in right-sided CRC.

## Key findings

- Right-sided CRC tumor cells show higher circadian rhythm disruption scores and a NONO-positive subpopulation.
- NONO⁺ tumor cells form a microenvironment with fibroblasts and act as efficient signal receivers.
- NONO enhances tumor-cell reception of signals from pro-tumorigenic fibroblasts, contributing to a malignant microenvironment.

## Abstract

The biological heterogeneity between left- and right-sided colorectal cancer (CRC) poses a significant clinical challenge and the underlying regulatory mechanisms remain elusive. As an emerging hallmark of cancer, the contribution of circadian rhythm disruption (CRD) to this side-specific heterogeneity is unclear. By integrating single-cell and spatial transcriptomic analyses, this study shows that tumor cells in right-sided CRC exhibit significantly higher CRD scores and identifies the emergence of a NONO-positive tumor-cell subpopulation (NONO⁺ TC) as a key molecular feature of this phenotype. Spatial analysis further confirms that this NONO⁺ TC forms a tightly co-localized microenvironment with fibroblasts in situ. Notably, cell–cell communication analyses indicate that NONO expression does not augment the signal-sending capacity of tumor cells but instead reprograms them into highly efficient signal receivers. These augmented incoming signals predominantly originate from the more pro-tumorigenic myofibroblastic cancer-associated fibroblast (myCAF) subtype, indicating that NONO⁺ TC are particularly sensitive to malignant stromal inputs. In conclusion, our study delineates the dual role of NONO as both a circadian regulator and a pro-tumorigenic signaling hub. By enhancing tumor-cell reception of CAF-derived signals, NONO links CRD to the formation of NONO⁺ TC niches and a malignant microenvironment in right-sided CRC, providing new mechanistic insight into the spatial heterogeneity of tumors.

The online version contains supplementary material available at 10.1186/s40364-025-00852-5.