bims-instec 2026-01-04 papers

Nat Commun. 2025 Dec 27.

Ribosome biogenesis as a potential therapeutic target in KRAS mutant colorectal cancer.

Yui Tanaka, Mizuho Sakahara, Hitomi Yamanaka, Yasuko Natsume, Daisuke Kusama, Kohei Kumegawa, Harunori Yoshikawa, Yuich Abe, Koji Okabayashi, Shimpei Matui, Yuko Kitagawa, Naohiko Koshikawa, Hiroki Osumi, Eiji Shinozaki, Satoshi Nagayama, Jun Adachi, Reo Maruyama, Ryoji Yao.

Molecular targeted therapies targeting KRAS signaling have significantly improved patient outcomes, but they have not achieved sufficient therapeutic efficacy in colorectal cancer (CRC). Here, we demonstrate that a subset of KRAS-mutant CRC cells transitions to a cellular state characterized by enhanced ribosome biogenesis upon KRAS signaling inhibition. The mitogen-activated protein kinase kinase inhibitor, trametinib, and AMG510 induce a cellular state characterized by a gene expression profile highly enriched for ribosome biogenesis. We find that they are vulnerable to the inhibition of RNA polymerase I, and they exhibit synergistic anti-tumor effects with trametinib in an autochthonous mouse model of intestinal tumors and human patient-derived organoids (PDOs). These observations demonstrate that high ribosome biogenesis induced by KRAS inhibition is indispensable to maintain this cellular state and is a potential therapeutic target. Overall, this study reveals novel mechanisms of drug tolerance to KRAS inhibition, thereby facilitating the development of new therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-67979-9

Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00541-0. [Epub ahead of print]

Adaptive plasticity in targeted therapy.

Vito Amodio, Giorgio Patelli, Alberto Bardelli.

In this issue of Cancer Cell, Zhang et al. show that dual KRAS-EGFR inhibition induces a reversible Paneth-like transition in colorectal cancer, sustaining mitogen-activated protein kinase (MAPK) reactivation through a SMAD1-FGFR3 axis. This reinforces emerging evidence that lineage remodeling underlies early adaptive escape from targeted therapy and carries potential clinical relevance.

DOI: https://doi.org/10.1016/j.ccell.2025.12.007

Cell Death Dis. 2025 Dec 29.

Targeting TRIM15-mediated Axin1 depolymerization suppresses Wnt signaling and inhibits colorectal cancer growth.

Hangfei Liang, Fanghong Zheng, Jincheng Wu, Han Zhou, Zhouyi Sun, Pengfei Zhang, Wei Wu, Guixin Zhu.

Axin1 plays a critical role in regulating the Wnt/β-catenin signaling pathway and cancer progression, and its polymerization is indispensable for the assembly of the β-catenin destruction complex. However, the mechanisms that control Axin1 polymerization are limited. Here, we reveal that TRIM15 interferes with the polymerization of Axin1, thereby promoting Wnt activation and colorectal cancer growth. Mechanistically, TRIM15 strongly interacts with Axin1 through its coiled-coil domain to disrupt the polymerization among Axin1 molecules. Manipulation of TRIM15 expression dramatically weakens Wnt signaling, cell proliferation, and tumor growth. Furthermore, conditional genetic ablation of Trim15 in mice inhibits tumor formation in both AOM/DSS-induced and ApcMin/+ colorectal cancer models. Notably, TRIM15 is also a Wnt target gene that forms a positive feedback loop in colon cancer cells. TRIM15 is highly expressed and is positively associated with β-catenin in colorectal cancer. More importantly, the simultaneous increase in Axin1 protein levels and its polymerization can synergistically induce apoptosis. Together, our study uncovers an important regulatory mechanism of Axin1 polymerization and implies that targeting TRIM15 provides a therapeutic strategy for colorectal cancer based on inhibiting Wnt signaling.

DOI: https://doi.org/10.1038/s41419-025-08400-7

STAR Protoc. 2025 Dec 29. pii: S2666-1667(25)00706-3. [Epub ahead of print]7(1): 104300

Protocol for high-throughput drug screening in 384-well 3D collagen cultures of SC colorectal cancer cells using colony morphology as a readout.

Sarah J Harmych, Thomas P Hasaka, Vivian Truong Jones, Joshua A Bauer, Bhuminder Singh.

Growth of cells in 3D cultures can more accurately predict in vivo behavior than the traditional 2D culture system, which lacks the complex environment of natural tissue. In this protocol, we provide steps to generate 3D collagen cultures in a 384-well format suited for high-throughput drug screens. We also detail our use of this protocol to assess morphological changes to 3D colonies of SC colorectal cancer cells, which serve as a robust readout for drug response. For complete details on the use and execution of this protocol, please refer to Harmych et al.1.

Keywords: cancer; cell culture; high-throughput screening; organoids

DOI: https://doi.org/10.1016/j.xpro.2025.104300

Anal Chem. 2025 Dec 28.

Filtration-Based Rapid ECM-Hydrogel Elimination Enables Robust MALDI MSI of Intestinal Organoids.

Fangyuan Zhang, Xinxin Shen, Jie Yuan, Jiayi Ye, Jian Sui, Huimin Tao, Jianfeng Xu, Yang Ye, Youhong Hu, Bo Wang, Jingqing Hu, Jia Liu.

The rapid development of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) offers a powerful approach for the 2D metabolic profiling of intestinal organoids. However, its application remains constrained by challenges in sample preparation. Conventional extracellular matrix (ECM)-based hydrogel removal methods, such as repeated centrifugation or enzymatic digestion, are labor-intensive and time-consuming, often causing structural disruption of organoids and degradation of metabolites, thereby compromising the spectral quality and metabolite coverage. In this study, we established a filtration-based rapid ECM-hydrogel elimination (FREE) method using a 70 μm filter, which reduced treatment time from 75 to 25 min while preserving organoid structural integrity, cell viability, and metabolic stability and, more importantly, improved data quality, with a 26.6% increase in metabolite coverage and enhanced signal intensity. Applying this workflow to an LPS-induced inflammatory intestinal organoid model, we observed spatial metabolic remodeling associated with epithelial polarity disruption. Notably, phosphatidylserine (PS) became enriched at the apical membrane, while phosphatidylethanolamine (PE) exhibited a basolateral side, suggesting a link between loss of polarity and early apoptotic signaling. Overall, FREE provides an efficient pretreatment strategy that enables MSI research on intestinal organoids to dissect the mechanisms of inflammation-associated metabolic remodeling.

DOI: https://doi.org/10.1021/acs.analchem.5c05415