bims-instec 2026-05-10 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2026–05–10
twenty papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Iron: Regulation, redox homeostasis, and ferroptosis in cancer.
Intestinal epithelial formyl peptide receptor 2 contributes to intestinal epithelium homeostasis and injury repair by regulating intestinal stem cell and transit-amplifying cell proliferation and differentiation.
A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer.
A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer.
Senescent endothelial cell-derived extracellular vesicles promote neoadjuvant chemoresistance in colorectal cancer via GPX4.
How ever-expanding organoids from epithelial stem cells were developed: A hypothesis-free approach.
Overcoming conditional immune resistance in MSS and pMMR colorectal cancer: A sequential gating framework for immunotherapy.
Targeting NUDT21-mediated alternative polyadenylation of oncogenes ameliorates colorectal cancer malignancy and metastasis.
Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer.
Oncogene-Mechanics Axis: KRAS G12C Confers Agility Enabling Malignant Mechano-responses to Peristalsis in Colorectal Cancer.
Linoleic Acid Reduces Paclitaxel Chemosensitivity in Colorectal Cancer.
Adipocyte-specific FFA2 deletion leads to increased adipose inflammation and is associated with altered intestinal lipid handling in mice.
Bioengineered systems to exploit tumor microenvironment metabolism.
ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis.
PRDM Proteins Orchestrate Colorectal Cancer Tumorigenesis.
Germline haploinsufficiency of MUTYH causes mutational signature SBS18 in multiple tumour types and specifically raises colorectal cancer risk.
All-in-One Fluorescent Probe: Enabling Simultaneous Tracking of Multiple Dynamic Organellar Perturbations during Ferroptosis.
Toward targeting the untargetable: A non-canonical EGFR-peptide-drug conjugate achieves potent antitumor activity in KRAS-mutant CRC.
'FILMing' the metabolic landscape of individual cell organelles.
Single-cell transcriptomic profiling of colorectal cancer brain metastasis.

Ferroptosis Oxid Stress. 2026 ;pii: 202526. [Epub ahead of print]2(3):

Iron: Regulation, redox homeostasis, and ferroptosis in cancer.

Chesta Jain, Yatrik M Shah.

  Iron is essential for cellular metabolism, redox balance, and proliferation, yet its redox activity generates reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Cancer cells exploit iron homeostasis mechanisms, including iron regulatory proteins, ferritinophagy, and hypoxia-inducible factors to maintain high intracellular iron, supporting metabolic reprogramming, antioxidant defenses, and therapy resistance. Iron-dependent lipid peroxidation drives ferroptosis, a regulated form of cell death uniquely dependent on iron. Ferroptosis is tightly controlled by metabolic and antioxidant pathways and mitochondrial ROS, as well as by lipid composition and polyunsaturated fatty acid availability. Ferroptosis also intersects with apoptosis and necroptosis, highlighting the central role of iron in cell fate and survival. Dysregulation of these pathways in cancer can sensitize cells to ferroptosis, creating a therapeutic vulnerability. Exploiting ferroptosis through modulation of iron availability, redox defenses, or lipid metabolism offers a promising anticancer strategy. However, tissue-specific iron dynamics, tumor heterogeneity, and interactions within the tumor microenvironment complicate clinical translation. Integrative approaches combining metabolic profiling, genetic analysis, and ferroptosis-targeted interventions will be critical to harness iron-dependent cell death while minimizing systemic toxicity. In this review, we explore the mechanisms through which cancer cells sustain high iron, evading associated toxicities and possible implications for integrating ferroptosis based therapies in clinical oncology.

Keywords:  Iron; ferroptosis; hypoxia; oxidative cell death

DOI:  https://doi.org/10.70401/fos.2026.0022
Life Metab. 2026 Jun;5(3): loaf045

Intestinal epithelial formyl peptide receptor 2 contributes to intestinal epithelium homeostasis and injury repair by regulating intestinal stem cell and transit-amplifying cell proliferation and differentiation.

Shuting Yu, Lele Song, Wunier, Shuyu Ouyang, Youpeng Ding, Lixing Zhan, Yi Arial Zeng, Yingying Le.

  Intestinal stem cells (ISCs) play critical roles in the self-renewal and regeneration of the intestinal epithelium under physiological conditions and after injury, respectively. However, the underlying mechanisms are not fully understood. In this study, we investigate the role of the G protein-coupled receptor formyl peptide receptor 2 (FPR2) in intestinal epithelium homeostasis and regeneration. In mice, knocking out Fpr2 in either intestinal epithelial cells (IECs) or ISCs significantly reduces villus height and crypt depth by impairing ISC and transit-amplifying (TA) cell proliferation and differentiation, primarily TA cell differentiation. Mechanistic studies using intestinal organoid culture and bulk and single-cell RNA sequencing revealed that activation of FPR2 promotes proliferation and differentiation of ISCs and TA cells by activating the wingless/integrated (Wnt), Notch, and Hippo signaling pathways via protein kinase C (PKC)-extracellular signal-regulated kinase (ERK). Under physiological conditions, the Wnt and Notch signaling pathways mediate the regulation of ISC proliferation and differentiation by FPR2. Fpr2 deficiency in mouse IECs exacerbates X-ray- and 5-fluorouracil-induced villus and crypt injury, and delays intestinal epithelium regeneration by reducing ISC and TA cell proliferation. Administering an FPR2 agonist to mice significantly increases survival rates and accelerates intestinal epithelium regeneration after irradiation. Taken together, these results demonstrate that intestinal epithelial FPR2 plays a key role in intestinal epithelium homeostasis and regeneration by promoting ISC and TA cell proliferation and differentiation. FPR2 is a potential therapeutic target against chemotherapy- and radiotherapy-induced intestinal injury.

Keywords:  Wnt pathway; formyl peptide receptor 2; intestinal epithelium homeostasis; intestinal epithelium injury repair; intestinal stem cell; transit-amplifying cell

DOI:  https://doi.org/10.1093/lifemeta/loaf045
Cell Rep Med. 2026 May 06. pii: S2666-3791(26)00193-X. [Epub ahead of print] 102776

A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer.

Julian Chua, Arshdeep Kaur, Fynnis Mitchell, Anneke Korver, Parnika Sakthivel, Elleine Allapitan, Mahdin Uddin, Areeba Maqsood, Naomi Chege, Aralia Leon-Coria, Constance A M Finney, Oliver F Bathe, Parham Minoo, Arshad Ayyaz.

  Immunotherapy remains largely ineffective in colorectal cancer (CRC), particularly in microsatellite stable (MSS) tumors, which represent the majority of cases. However, the complexity of intratumoral heterogeneity has made it difficult to define tumor-intrinsic programs that drive immune resistance. Here, we identify a cancer cell population that emerges predominantly in advanced-stage MSS CRCs. These cells exhibit stem-like features but aberrantly activate a WNT-inhibitory transcriptional program marked by high NOTUM expression. We term these cells WNT/β-catenin inhibitory cancer cells (WICCs). WICCs are enriched in immune-excluded tumors, correlate with reduced CD8+ T cell infiltration, and are induced in both primary human CRC tumors and patient-derived tumoroids. Selective ablation of WICCs or genetic knockout of NOTUM enhances CD8+ T-cell-mediated cytotoxicity, uncovering a tumor-intrinsic mechanism of immune evasion and nominating the WICC-NOTUM axis as a selective and tractable therapeutic target to overcome immunotherapy resistance in CRC.

Keywords:  CD8(+) T cells; NOTUM; WNT signaling; cancer-stem-like cells; colorectal cancer; immunosuppression; immunotherapy; microsatellite stable; single-cell genomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2026.102776
Nat Cancer. 2026 May 07.

A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer.

Melanie Heinlein, Ginny X Li, Noelyn Kljavin, Amanda R Moore, Brian Biehs, Liming Tao, Soufiane Boumahdi, Farnaz Mohammadi, Minyi Shi, Yuxin Liang, Hartmut Koeppen, Nicolò Riggi, Robert Piskol, Frederic J de Sauvage.

Colorectal cancer (CRC), a leading cause of cancer-related mortality due to distant metastases, is largely driven by activating mutations in the WNT and mitogen-activated protein kinase (MAPK) pathways. Understanding the mechanism underlying the metastatic process is essential for developing effective treatments. Using serial in vivo orthotopic passaging, we developed an immunocompetent mouse model of metastatic CRC. Highly metastatic tumor cells exhibited chromosomal amplifications in MAPK pathway genes, resulting in increased MAPK pathway activity and suppression of WNT-associated transcriptional programs, including stem cell genes. Pharmacological inhibition of mutant KRASG12D led to a reduction in the MAPK-high-WNT-low transcriptional state and decreased both lung and liver metastases. Analysis of CRC patient data revealed that the metastatic gene signature associated with the MAPK-high-WNT-low state correlated with poorer survival outcomes. These findings underscore the plasticity of metastasis-initiating cells in CRC driven by the opposing roles of MAPK and WNT signaling, despite their synergy observed during colon tumorigenesis.

DOI: https://doi.org/10.1038/s43018-026-01155-w
Commun Biol. 2026 May 05.

Senescent endothelial cell-derived extracellular vesicles promote neoadjuvant chemoresistance in colorectal cancer via GPX4.

Kunpeng Jia, Yuxin Ding, Menglei Jin, Qi Yang, Xinyu Wang, Yujie Yan, Jiao Xiang, Ruoqi Zhang, Jun Fang, Jingxin Jiang, Danting Wang, Fengbo Huang, Jianming Hu, Jian Huang, Yeting Hu, Zhigang Chen.

Chemotherapy resistance remains a major challenge in advanced colorectal cancer (CRC), with chemotherapy-induced senescence playing a key role. While cancer cell senescence has been extensively studied, the contribution of stromal components, particularly vascular endothelial cells, remains unclear. Here, we analyze 77 CRC patients undergoing neoadjuvant chemotherapy and find that favorable responders exhibit well-defined vascular lumens, whereas poor responders show an increase in senescent endothelial cells (senEndo), as revealed by single-cell transcriptomics and immunofluorescence. Chemotherapy-induced senescence reduces GPX4 ubiquitylation in senEndo, leading to its accumulation and extracellular vesicle transfer to CRC cells, where it inhibits ferroptosis and promotes chemoresistance. In vitro and in vivo models demonstrate that targeting GPX4 with the ferroptosis activator RSL3 restores chemotherapy sensitivity. These findings identify a novel mechanism of chemoresistance mediated by senEndo-derived GPX4 in extracellular vesicles and highlight the potential of ferroptosis induction, alone or in combination with senolytic agents, to improve 5-Fu/oxaliplatin-based CRC therapies.

DOI: https://doi.org/10.1038/s42003-026-10183-2
Cell Stem Cell. 2026 May 07. pii: S1934-5909(26)00141-4. [Epub ahead of print]33(5): 722-725

How ever-expanding organoids from epithelial stem cells were developed: A hypothesis-free approach.

Hans Clevers.

DOI: https://doi.org/10.1016/j.stem.2026.04.001
Crit Rev Oncol Hematol. 2026 May 01. pii: S1040-8428(26)00240-4. [Epub ahead of print]223 105353

Overcoming conditional immune resistance in MSS and pMMR colorectal cancer: A sequential gating framework for immunotherapy.

Husni Farah, Djamila Polatova, Jasur Rizaev, Faez Ahmed Mhdy, Faris Anad Muhammad, Laxmidhar Maharana, Neeraj Bainsal, Ritesh Singh.

  Microsatellite stable and mismatch repair proficient colorectal cancer (CRC) represents the largest population of patients exposed to immune checkpoint inhibitors, yet remains largely refractory to these therapies. Resistance is commonly attributed to low tumor mutational burden or limited neoantigenicity. However, this explanation is insufficient in light of accumulating clinical, transcriptional, and spatial profiling data demonstrating the presence of immune cells, antigen expression, and inducible immune signaling in a substantial fraction of MSS tumors. In this Review, we propose that immunotherapy failure in MSS and pMMR CRC reflects a hierarchical immune gating problem rather than intrinsic immune indifference. We outline a sequential model in which immune priming, physical access of effector cells to tumor epithelial compartments, and suppression by stromal, myeloid, and metabolic programs constitute ordered and rate-limiting steps that must be relieved before immune checkpoint blockade can exert clinical activity. This framework reconciles decades of negative clinical trials with emerging conditional successes observed using epigenetic priming, stromal and vascular remodeling, myeloid reprogramming, and microbiome-modulating strategies. By reframing resistance as a dynamically enforced and therapeutically tractable immune state, this Review provides a decision shaping framework for rational combination therapy, treatment sequencing, and biomarker guided immunotherapy development in MSS and pMMR CRC.

Keywords:  Immune checkpoint blockade; Immune priming; Immunotherapy resistance; Microsatellite stable colorectal cancer; Therapeutic sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105353
Br J Cancer. 2026 May 06.

Targeting NUDT21-mediated alternative polyadenylation of oncogenes ameliorates colorectal cancer malignancy and metastasis.

Shih-Chieh Lin, Ya-Chuan Tsai, Jui-Lin Wang, Hsian-Jean Chin, Ching-Chin Tsai, Shin-Chih Lin, Yi-Syuan Lin, Bo-Wen Lin, Shaw-Jenq Tsai.

BACKGROUND: Colorectal cancer (CRC) is a disease leading cause of death worldwide. Lacking molecular markers for early detection and suitable candidates for targeted therapies are two main reasons for causing CRC malignancy.
OBJECTIVES: Exploring the role of NUDT21 in colorectal cancer metastasis.
METHODS: A systematic bioinformatic analysis identified key genes involved in colorectal cancer, which were subsequently validated through loss-of-function and gain-of-function experiments conducted both in vitro and in vivo.
RESULTS: Overexpression of nucleoside diphosphate linked moiety X hydrolases-type motif 21 (NUDT21), a critical factor that regulates alternative polyadenylation, is observed in malignant polyps and in human and mouse CRC. Survival analysis reveals that high level of NUDT21 is associated with poor prognosis. NUDT21 knockdown not only inhibits cell growth but also reduces malignancy traits like anchorage-independent growth and cancer stemness. RNA-seq and RIP-seq results show NUDT21 preferentially binds to the proximal alternative polyadenylation site of numerous oncogenes to promote their expression and thus drive the progression of CRC. Treatment with re-purposing drugs targeting NUDT21 exhibit therapeutic potential in cell culture, organoid, orthotopic, and patient-derived xenografted CRC models.
CONCLUSIONS: These findings demonstrate that NUDT21 is a critical regulator of colon cancer progression and a promising therapeutic target for CRC.

DOI: https://doi.org/10.1038/s41416-026-03451-9
Clin Cancer Res. 2026 May 08.

Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer.

Hey Min Lee, Zhao Zheng, Alexey Sorokin, Chi Wut Wong, Stefania Napolitano, Saikat Chowdhury, Preeti Marie Kanikarla, Anand K Singh, Veena Kochat, Christopher A Bristow, Sanjana Srinivasan, Michael Peoples, Emre Arslan, Jumanah Yousef Alshenaifi, Oscar E Villarreal, Van K Morris, John Paul Shen, Funda Meric-Bernstam, Abhinav K Jain, Natalie Wall Fowlkes, Amanda Anderson, David G Menter, Ajay Kumar Saw, Kunal Rai, Scott Kopetz.

PURPOSE: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC), particularly in the BRAFV600E-mutated metastatic subtype, which uniquely exhibits a strong epigenetic phenotype. Building on this epigenetic vulnerability, bromodomain 2, a reader of H3K27ac-marked enhancers, was found to be synthetically lethal with BRAF + EGFR inhibition.
EXPERIMENTAL DESIGN: We evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive transcriptomic and chromatin profiling.
RESULTS: BET plus standard MAPK inhibitors demonstrated improved efficacy against BRAFV600E CRC and selective improvements against RAS-mutant CRC in vivo. This combination induced a more profound downregulation of the MAPK signaling pathway than MAPK inhibition alone. The loss of activation signal on H3K27ac-marked enhancers led to the dysregulation of core-regulatory circuitries, especially the MAPK downstream E26 transformation-specific transcription factor family and MYC. Single-nucleus RNA+ATAC sequencing distinguished differential transcriptomic and chromatin dynamics at the cell-type level. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream transcription factors. Conversely, an abundance of dedifferentiated cell populations emerged after MAPK or combination inhibition, suggesting therapy-induced cell-state switching and adaptation.
CONCLUSION: Our work demonstrates that BET inhibition improves MAPK signaling blockade through profound epigenetic reprogramming of core transcription factor circuits. These findings provide a preclinical rationale for the evaluation of BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic CRC (NCT06102902).

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4370
bioRxiv. 2026 May 01. pii: 2026.04.28.721453. [Epub ahead of print]

Oncogene-Mechanics Axis: KRAS G12C Confers Agility Enabling Malignant Mechano-responses to Peristalsis in Colorectal Cancer.

Astha Lamichhane, Vsevolod Cheburkanov, Mykyta Kizilov, Abhinav Shenoy, Audrey G Head, Vladislav Yakovlev, Shreya Artha Raghavan.

Oncogene activity and mechanical forced individually and collective drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both ehalthy intestinal cells and KRAS G12C cells sensed peristalsis via ERK phosphorylation, their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5+ cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy controls. Using Brillouin microscopy, we discovered that KRAS G12C induced a more agile and deformable mechano-phenotype by lowering intracellular viscosity, a state further amplified by peristalsis. This agility allowed KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic inhibition of KRAS G12C reverse the mechano-phenotype, while introducing KRAS G12C into healthy cells recapitulated it. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell's mechanical state could be a powerful complement to emerging KRAS-directed therapies.

DOI: https://doi.org/10.64898/2026.04.28.721453
Drug Des Devel Ther. 2026 ;20 577058

Linoleic Acid Reduces Paclitaxel Chemosensitivity in Colorectal Cancer.

Bingwen Zhou, Jinjin Pan, Mengjie Wang, Peng Zhou, Zhili Li, Jingwei Cui, Chuyue Huang, Lu Wang, Zhimin Fan.

   Purpose: Paclitaxel, a natural diterpenoid compound derived from Taxus species, is one of the most successful plant-based anticancer drugs and has been widely applied in the treatment of various solid tumors. In recent years, emerging evidence has suggested its potential efficacy in refractory or advanced colorectal cancer (CRC), particularly in patients resistant to standard first-line chemotherapy such as 5-fluorouracil (5-FU). However, responses to paclitaxel in CRC are heterogeneous. This study aimed to elucidate the metabolic determinants underlying the heterogeneous response of CRC to paclitaxel and to identify serum metabolites associated with therapeutic response.
Patients and Methods: Integrated serum metabolomic profiling was performed in patient-derived tumor organoid (PDTOs, n=18), combined with drug sensitivity assays and in vivo validation using mouse xenograft models. An analysis was conducted to sensitivity of paclitaxel, followed by targeted metabolomic quantification and pathway enrichment to identify key metabolites influencing paclitaxel efficacy.
Results: Linoleic acid (LA) was identified as a serum metabolite significantly correlated with reduced paclitaxel sensitivity. Elevated LA levels attenuated paclitaxel-induced G2/M cell cycle arrest and reduced cytotoxicity by altering microtubule dynamics. Functional validation in CRC cell lines and animal models further confirmed that LA diminished the antitumor effect of paclitaxel, supporting a metabolism-mediated mechanism of chemoresistance.
Conclusion: This study identifies serum linoleic acid as a metabolism-related candidate biomarker associated with paclitaxel resistance in CRC. These findings highlight the potential clinical relevance of metabolic factors in modulating chemotherapy response and suggest that LA may have potential relevance for patient stratification in future studies of paclitaxel response in CRC.

Keywords:  biomarker; chemosensitivity; colorectal cancer; patient derived tumor organoids; personalized treatment; serum metabolomics

DOI:  https://doi.org/10.2147/DDDT.S577058
Physiol Rep. 2026 May;14(9): e70875

Adipocyte-specific FFA2 deletion leads to increased adipose inflammation and is associated with altered intestinal lipid handling in mice.

Chioma Nnyamah, James Boyett, Barton Wicksteed, Nupur Pandya, Kai Xu, Irene Corona-Avila, Nadia Sweis, Marissa St George, Laura J Den Hartigh, Abeer M Mahmoud, Yuwei Jiang, Jose Cordoba-Chacon, Medha Priyadarshini, Brian T Layden.

  Obesity and related metabolic disorders are often characterized by chronic adipose tissue inflammation, driving systemic insulin resistance and general metabolic dysfunction. Free Fatty Acid Receptor 2 (FFA2) has emerged as a potential modulator of adipocyte function, inflammation, and metabolism. To investigate the role of FFA2 expressed in the adipose tissue, we generated adipose-specific FFA2 knockout mice (Adipoq-F2-KO) and assessed metabolic outcomes under standard laboratory chow and high-fat, high-sugar Western diet conditions, with and without dietary fiber supplementation. We found that adipose-specific FFA2 deletion had minimal metabolic consequences under standard dietary conditions but significantly reduced body weight and adiposity when mice were fed a fiber (fructooligosaccharide)-supplemented Western diet. Subsequent fecal analyses and transcriptomic profiling indicated impaired intestinal lipid absorption as the primary driver of reduced adiposity, suggesting disrupted adipose-intestinal communication. Unexpectedly, the lighter Adipoq-F2-KO mice also exhibited heightened adipose inflammation, characterized by increased macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, in vitro loss-of-function experiments in adipocytes revealed that FFA2 knockdown impaired adipocyte maturation, lipid storage, and anti-inflammatory signaling. Additional studies using intestinal epithelial cells exposed to adipocyte-conditioned media implicated adipose-derived signals in driving intestinal dysfunction. Collectively, our findings highlight adipose-specific FFA2 as critical in regulating adipose tissue inflammation, lipid metabolism, and inter-organ communication.

Keywords:  adipose tissue; dietary fiber; free fatty acid receptor 2; gut‐adipose axis; metabolic dysfunction; short chain fatty acids

DOI:  https://doi.org/10.14814/phy2.70875
Trends Cancer. 2026 May 07. pii: S2405-8033(26)00078-6. [Epub ahead of print]

Bioengineered systems to exploit tumor microenvironment metabolism.

Christine Sanganoo, Ilaria Caturegli, Zachary Mattes, Jordan Ryan, Wilson W Wong, Mark W Grinstaff.

  Our understanding of cancer metabolism has afforded the opportunity to develop therapies specific to tumor metabolic dysregulation. While molecular therapeutics targeting cancer metabolism have found success in the clinic, bioengineering approaches are nascent. Here, we describe key metabolic pathways and their genetic dysregulations in the tumor microenvironment (TME) that are ripe for intervention. We examine bioengineered biomaterial and cellular systems that harness the metabolic and immune landscape of the TME to target metabolic dependencies of tumor growth. These therapeutic strategies include, for example, preventing the uptake of essential metabolites, delivering metabolic inhibitors, and restoring an immunostimulating environment. With a focus toward clinical applications and tolerability, we identify key limitations and conclude with future directions.

Keywords:  antimetabolite delivery; biomaterials; cancer metabolism; immunosuppressive metabolite modulation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2026.04.003
Signal Transduct Target Ther. 2026 May 05. pii: 166. [Epub ahead of print]11(1):

ENO2 drives tumor cell-induced M2 macrophage polarization to promote colorectal cancer liver metastasis.

Junwei Tang, Zhihao Chen, Dongsheng Zhang, Kangpeng Jin, Hengjie Xu, Chuanxin Tian, Jinling Duan, Sheng Yang, Qingyang Sun, Yifei Feng, Xiaowei Wang, Dan Xie, Yueming Sun.

Liver metastasis is the primary cause of mortality in colorectal cancer (CRC) patients. To decipher the underlying mechanisms, we performed single-cell RNA sequencing (scRNA-seq) on paired primary colorectal tumors, adjacent tissues and liver metastases from three CRC liver metastasis (CRLM) patients, alongside colorectal tumors and adjacent tissues from three non-metastatic CRC patients. Our analysis revealed a significant enrichment of Enolase 2-expressing (ENO2⁺) cancer cells in CRLM patients compared to their non-metastatic counterparts. Functional characterization, supported by bioinformatics and murine models, demonstrated that ENO2⁺ cancer cells exhibit enhanced epithelial-mesenchymal transition (EMT) and are critical drivers of CRLM. Mechanistically, the ENO2 protein directly binds to macrophage migration inhibitory factor (MIF) within cancer cells, stabilizing MIF by inhibiting its C-terminus of Hsc70-Interacting Protein (CHIP)-mediated ubiquitination and degradation. This ENO2-MIF interaction activates MIF signaling, fostering robust tumor cell-macrophage crosstalk that promotes M2 macrophage polarization, which is validated by spatial transcriptomics showing the colocalization of ENO2⁺ cancer cells and M2 macrophages. Crucially, both organoid and in vivo models confirmed that ENO2 in CRC cells is essential for inducing M2 macrophage polarization via the MIF pathway, thereby facilitating liver metastasis. Knockout of ENO2 significantly suppressed tumor growth and liver metastasis in mouse models. An inhibitor of the ENO2-MIF interaction, pyrithioxin, can effectively reduce the burden of liver metastasis in mice. Collectively, our findings identify ENO2 as a key driver of CRLM by stabilizing MIF to orchestrate M2 macrophage polarization, highlighting the ENO2-MIF axis as a promising therapeutic strategy for CRLM.

DOI: https://doi.org/10.1038/s41392-026-02732-2
Int J Mol Sci. 2026 Apr 09. pii: 3392. [Epub ahead of print]27(8):

PRDM Proteins Orchestrate Colorectal Cancer Tumorigenesis.

Erika Di Zazzo, Carmela Sorrentino, Monica Rienzo, Donatella Fiore, Maria Chiara Proto, Amelia Casamassimi, Patrizia Gazzerro, Ciro Abbondanza.

  Colorectal cancer (CRC) is a heterogeneous disease driven by complex genetic, epigenetic, and microenvironmental alterations. Members of the PR domain-containing (PRDM) protein family have emerged as context-dependent regulators of CRC initiation, progression, tumor cell plasticity, immune modulation, and therapeutic response. Accumulating evidence highlights divergent roles for PRDM proteins as tumor suppressors, oncogenes, or isoform-dependent dual-function regulators. Collectively, PRDM family members represent a central node of transcriptional/epigenetic control in CRC biology, with significant potential as biomarkers for early detection, prognosis, and treatment stratification, as well as promising candidates for epigenetic and pathway-directed therapeutic strategies.

Keywords:  PRDM; cancer biomarkers; colorectal cancer; consensus molecular subtypes (CMS); oncogene; tumor suppressor

DOI:  https://doi.org/10.3390/ijms27083392
NPJ Precis Oncol. 2026 May 06.

Germline haploinsufficiency of MUTYH causes mutational signature SBS18 in multiple tumour types and specifically raises colorectal cancer risk.

Kitty Sherwood, Juan Fernandez-Tajes, Güler Gül, Steve Thorn, Joseph C Ward, James F Wilson, Claire Palles, D Timothy Bishop, Richard S Houlston, Malcolm G Dunlop, Ian P M Tomlinson.

The MUTYH base excision repair protein corrects oxidative DNA damage. Bi-allelic germline MUTYH mutations cause a rare, Mendelian recessive syndrome of colorectal adenomas, duodenal polyps and colorectal cancer (CRC), in which tumours have excess somatic C:G > A:T mutations and the mutational signature SBS36. Signature SBS18, which resembles SBS36, is common in sporadic CRCs and other cancers. Increased risks of CRC and other cancers have been reported in germline MUTYH heterozygotes (mono-allelic mutation carriers, frequency 2-3%), but the existence of these associations and underlying mechanism have remained controversial. Compared with MUTYH-wildtype individuals, CRCs from MUTYH heterozygotes had ~2.5-fold excess of signature SBS18, increased C:G > A:T transversions (including in driver genes) and raised mutation burden. These observations resulted from MUTYH haploinsufficiency, rather than somatic loss of the wildtype allele, contrary to previous suggestions. Hypermutation probably begins before cancer initiation. In a case-control analysis, we found approximately 1.4-fold elevated risk of CRC in MUTYH heterozygotes, causally mediated through increased SBS18. The association between MUTYH heterozygosity and SBS18 was also present in many extra-colonic cancers, including other gastrointestinal tumours, but the raised SBS18 did not detectably increase the risk of these cancers. Germline heterozygotes for another base excision repair gene, MBD4, showed equivalent associations for SBS1, C:G > T:A mutations and CRC risk. Mutational signatures in cancers can result in part from non-rare germline variation in DNA repair. The specific effect of MUTYH heterozygosity on CRC risk plausibly reflects the high baseline levels of oxidative damage and SBS18 activity in the colorectum.

DOI: https://doi.org/10.1038/s41698-026-01425-x
Anal Chem. 2026 May 06.

All-in-One Fluorescent Probe: Enabling Simultaneous Tracking of Multiple Dynamic Organellar Perturbations during Ferroptosis.

Tian Jiang, Mei-Lin Liu, Lin Lei, Jia-Yao Zhang, Zi-Xin Gong, Xiao-Qi Yu, Kun Li, Jin-Ku Bao, Chuan-Fang Wu, Kang-Kang Yu.

Ferroptosis is a regulated form of cell death driven by lipid peroxidation, involving intricate crosstalk between subcellular organelles and dynamic microenvironmental perturbations. However, this mechanism remains incompletely elucidated due to the lack of versatile tools enabling the simultaneous monitoring of multiple organelles and their microenvironments. Herein, we report a novel single fluorescent probe (ATBI) that allows concurrent discrimination and visualization of three key subcellular organelles: mitochondria, lysosomes, and lipid droplets (LDs). ATBI lights up mitochondria/lysosomes (∼719 nm) and LDs (∼425 nm) simultaneously with high fidelity at distinctly separated emission wavelengths. Notably, mitochondria and lysosomes can be effectively distinguished by their distinct morphological features and fluorescence lifetimes, while changes in viscosity within mitochondria/lysosomes can be further quantified based on lifetime variations. Using this multifunctional probe, we visualized the dynamic process of Erastin-induced ferroptosis: LD accumulation, increased lysosomal viscosity, and decreased mitochondrial viscosity. Furthermore, we demonstrated that SLC7A11, a key regulatory factor of ferroptosis, restores the normal morphology and viscosity homeostasis of these organelles, highlighting the critical role of maintaining subcellular organellar morphology and microenvironmental stability in resisting ferroptosis.

DOI: https://doi.org/10.1021/acs.analchem.5c08096
J Control Release. 2026 May 06. pii: S0168-3659(26)00396-2. [Epub ahead of print] 114993

Toward targeting the untargetable: A non-canonical EGFR-peptide-drug conjugate achieves potent antitumor activity in KRAS-mutant CRC.

Shachar Ayali, Akash Panja, Pousali Mitra, Yashaswi Dutta Gupta, Dror Tobi, Andrii Bazylevich, Baruch Brenner, Zoya Cohen, Ayelet Rosenberg Ayale, Elimelech Nesher, Gary Gellerman, Bat Chen R Lubin.

  Colorectal cancer (CRC) harboring KRAS mutations remains a major therapeutic challenge, as resistance to EGFR directed signaling inhibitors persists despite receptor expression. We aimed to establish a delivery-based therapeutic strategy that bypasses EGFR signaling inhibition by exploiting the receptor as an internalization gate. We report the development of a peptide-drug conjugate (PDC) that exploits non-canonical EGFR engagement to enable tumor selective delivery of the cytotoxic payload SN38. Computational modeling demonstrates stable binding of the P6 peptide within a non-canonical extracellular cavity between domains I and III of EGFR, distinct from the classical EGF binding site, supporting a potential allosteric interaction mechanism. The resulting PDC exhibits preferential cellular uptake and cytotoxicity in KRAS mutant CRC cells compared with normal colon epithelial cells, despite EGFR expression in both, demonstrating tumor selective internalization driven by cellular context and receptor density. P6-SN38 significantly inhibits cancer cell migration in vitro, further supporting its anti-tumor activity beyond cytotoxicity. PDC treatment significantly suppresses tumor growth in in vivo KRAS mutant xenograft model, demonstrating superior efficacy compared with cetuximab-based regimens and controls, without observable body weight loss. This strategy uses EGFR as a delivery portal instead of a signaling target, enabling KRAS independent anti-tumor activity. These findings indicate a non-canonical EGFR mediated delivery approach with potential translational relevance for the treatment of therapy resistant CRC.

Keywords:  CRC; EGFR; KRAS; Peptide–drug conjugate; SN38; Targeted cancer therapy; Topo I inhibitor

DOI:  https://doi.org/10.1016/j.jconrel.2026.114993
Nat Methods. 2026 May 07.

'FILMing' the metabolic landscape of individual cell organelles.

DOI: https://doi.org/10.1038/s41592-026-03091-0
Discov Oncol. 2026 May 06.

Single-cell transcriptomic profiling of colorectal cancer brain metastasis.

Kehong Wei, Qing Gao, Chaoliang Xu, Deshen Pan, Yurui He, Yaohua Liu, Deshui Jia, Cheng Chang.

   BACKGROUND: Brain metastasis from colorectal cancer (CRC) remains a highly lethal disease. However, the molecular mechanisms driving CRC brain metastasis are not fully characterized.
METHODS: Employing single-cell RNA sequencing (scRNA-seq), we delineated the cellular atlas of a resected CRC brain metastasis specimen and particularly focused on the tumor cell compartment.
RESULTS: Our scRNA-seq analysis profiled 4,748 high-quality single cells from a CRC brain metastasis sample. Tumor cells constituted the dominant population. Within the immune compartment, myeloid cells, including macrophages and monocytes, represented the predominant components of the metastatic microenvironment. In addition, key elements of the blood-tumor barrier, such as endothelial cells and pericytes, were characterized and implicated in brain metastasis. Tumor cells showed phenotypic plasticity, with transcriptional dynamics consistent with a mesenchymal-to-epithelial transition. Notably, a highly proliferative tumor cell subset with elevated KMT2B expression was identified. Functional analyses demonstrated that KMT2B depletion significantly impaired CRC cell proliferation and migration. Mechanistically, KMT2B promoted metastatic potential partly by upregulating MEX3A expression. Furthermore, high expression levels of KMT2B and MEX3A were associated with poor prognosis in both CRC and pan-cancer patients.
CONCLUSION: Collectively, this study identifies KMT2B as a potential driver of CRC brain metastasis and highlights it as a candidate therapeutic target for CRC treatment.

Keywords:  Brain metastasis; Colorectal cancer; Single-cell RNA sequencing

DOI:  https://doi.org/10.1007/s12672-026-05159-x