bims-instec 2025-08-31 papers

bims-instec

Biomed News

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

Issue of 2025–08–31
25 papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Protective role of epithelial deoxyhypusine synthase in colorectal carcinogenesis caused by deletion of the adenomatous polyposis coli gene.
Gut feeling: extracellular vesicles dictate liver's susceptibility to colorectal cancer metastasis.
A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer.
Injury-induced intestinal stem cell renewal requires capillary morphogenesis gene 2.
CRCs-CAFs crosstalk-targeted nano-delivery system reprograms tumor microenvironment for oxaliplatin resistance reversing and liver metastasis inhibition in colorectal cancer.
Mechanical confinement governs phenotypic plasticity in melanoma.
Liver regeneration-associated hepatocellular YAP1 activation prevents colorectal cancer liver metastasis through glutamine competition.
Understanding cancer cell plasticity: EMT, respecialisation, and therapeutic opportunities.
Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer.
Multiple organs exhibit exacerbated cachexia in male mice with colon cancer than females.
Colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth.
Lymph nodes molecular subtypes unravel lymph nodes heterogeneity and clinical implications in colorectal cancer.
Oncometabolite 5-IP7 inhibits inositol 5-phosphatase to license E-cadherin endocytosis.
One-carbon metabolic pathway is a novel molecular signature for CD44-positive intestinal-type gastric cancer.
PROCC: a predictive score to identify KRAS wild type metastatic colorectal cancer patients who are likely to obtain survival benefit from panitumumab treatment.
ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L.
Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
Endocytosis is essential for cysteine-deprivation-induced ferroptosis.
STAT3 sustains tumorigenicity following mutant KRAS ablation.
Lipoproteins: Friend and foe for ferroptosis?
A Deep Learning Approach for Tracking Colorectal Cancer-Derived Extracellular Vesicles in Colon and Lung Models.
3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer.
Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.
Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.
GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer.

Cancer Lett. 2025 Aug 24. pii: S0304-3835(25)00572-5. [Epub ahead of print]633 218002

Protective role of epithelial deoxyhypusine synthase in colorectal carcinogenesis caused by deletion of the adenomatous polyposis coli gene.

Alain P Gobert, Caroline V Hawkins, Lydia A Snyder, Kamery J Williams, Daniel P Barry, Margaret M Allaman, Mohammad Asim, Kara M McNamara, Shane M Carey, Alberto G Delgado, Regina N Tyree, Kristie L Rose, Yu Wang, Shilin Zhao, Olivier Boutaud, Irène Zagol-Ikapitte, M Blanca Piazuelo, M Kay Washington, Lori A Coburn, Keith T Wilson.

  Mutations in the adenomatous polyposis coli (APC) gene lead to the formation of adenomatous polyps in the colon that can evolve into carcinoma. We have reported that deoxyhypusine synthase (DHPS), the rate-limiting enzyme for the synthesis of the amino acid hypusine on the eukaryotic translation initiation factor 5A, plays a major role in intestinal homoeostasis. Here, we investigated the role of hypusination in sporadic colorectal cancer (CRC). GEO database analyses revealed increases in polyamine metabolism genes, including DHPS, in human CRC. Tumors exhibited increased immunostaining for DHPS compared non-tumor tissues. Then, we generated mice with tamoxifen-inducible disruption of both Apc and Dhps in intestinal epithelial cells. Compared to animals with deletion of Apc only, survival and body weight loss were worsened in mice with specific deletion of both Apc and Dhps. Moreover, these animals had increased tumor number, tumor burden, and adenomas with low-grade or high-grade dysplasia. Differential label-free quantitative proteomic analysis on colonic epithelial cells demonstrated that DHPS activity in the tumors supported the translation of enzymes implicated in detoxification of deleterious electrophiles. Thus, tumors from mice with Apc and Dhps deletion exhibited increased malondialdehyde-dilysyl crosslinks. Further, the exacerbated tumorigenesis in mice with deletion of Apc and Dhps was significantly reduced by treatment with a scavenger of electrophiles, 2-hydroxybenzylamine. Thus, epithelial hypusination is essential to dampen the initiation of adenoma formation, notably by reducing the deleterious effects of reactive aldehydes. Strategies to enhance hypusination, such as by spermidine supplementation, may have potential for chemoprevention of CRC.

Keywords:  Carcinogenesis; Colon; Colorectal cancer; Deoxyhypusine synthase; Hypusine; Polyamine; Reactive aldehyde

DOI:  https://doi.org/10.1016/j.canlet.2025.218002
Gut. 2025 Aug 25. pii: gutjnl-2025-336108. [Epub ahead of print]

Gut feeling: extracellular vesicles dictate liver's susceptibility to colorectal cancer metastasis.

Micol Eleonora Fiori.



Keywords:  COLORECTAL CANCER; LIPID METABOLISM; LIVER METASTASES

DOI:  https://doi.org/10.1136/gutjnl-2025-336108
Commun Biol. 2025 Aug 25. 8(1): 1278

A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer.

Shuo Wang, Shiqi Diao, Hyungdong Kim, Jia Yi Zou, Ke Ke Li, Antonis E Koromilas.

In tumorous conditions, STAT1, traditionally recognized for its anti-tumor role in immunology, exhibits pro-survival characteristics, though unclear mechanisms. Investigating STAT1 function in isogenic colorectal tumor cells with wild-type or mutant KRAS, we found that STAT1 specifically promotes tumor survival and proliferation with mutant KRAS. Gene expression profiling revealed that STAT1 promotes the expression of sterol and lipid biosynthesis genes in these cells. This effect depends on STAT1 phosphorylation at S727, which upregulates SREBP1 and SREBP2 to drive de novo lipid production. In mutant KRAS cells, STAT1 amplifies the mevalonate pathway, maintaining its S727 phosphorylation and establishing a positive feedback loop through the transcription factors YAP1 and TEAD4, further driving lipid biosynthesis and tumor growth. This STAT1-YAP1 axis promotes mutant KRAS tumor cells' resistance to mevalonate pathway inhibitors, which can be overcome by pharmacologically targeting the YAP1-TEAD interaction. Moreover, this axis contributes to the inherent resistance of mutant KRAS colon cancer cells to EGFR-targeted therapy. Together, these findings identify the STAT1-YAP1 pathway as a critical mediator of therapy resistance and a promising therapeutic target in mutant KRAS colorectal cancer.

DOI: https://doi.org/10.1038/s42003-025-08740-2
EMBO Mol Med. 2025 Aug 22.

Injury-induced intestinal stem cell renewal requires capillary morphogenesis gene 2.

Lucie Bracq, Audrey Chuat, Béatrice Kunz, Olivier Burri, Romain Guiet, Julien Duc, Nathalie Brandenberg, F Gisou van der Goot.

  Patients with the rare genetic disorder Hyaline Fibromatosis Syndrome (HFS) often succumb before 18 months of age due to severe diarrhea. As HFS is caused by loss-of-function mutations in the gene encoding capillary morphogenesis gene 2 (CMG2), these symptoms highlight a critical yet unexplored role for CMG2 in the gut. Here, we demonstrate that CMG2 knockout mice exhibit normal colon morphology and no signs of inflammation until the chemical induction of colitis. In these conditions, the colons of knockout mice do not regenerate despite previously experiencing similarly severe colitis, due to an inability to replenish their intestinal stem cell pool. Specifically, CMG2 knockout impairs the transition from fetal-like to Lgr5+ adult stem cells, which is associated with a defect in ß-catenin nuclear translocation. Based on our findings, we propose that CMG2 functions as a context-specific modulator of Wnt signaling, essential for replenishing the pool of intestinal stem cells following injury. This study provides new insights into the molecular mechanisms underlying lethal diarrhea in HFS and offers a broader understanding of fetal-like regenerative responses.

Keywords:  Colitis; Fetal-like Stem Cells; Lgr5; Regeneration; Wnt Signaling

DOI:  https://doi.org/10.1038/s44321-025-00295-3
Bioact Mater. 2025 Dec;54 126-143

CRCs-CAFs crosstalk-targeted nano-delivery system reprograms tumor microenvironment for oxaliplatin resistance reversing and liver metastasis inhibition in colorectal cancer.

Heshi Liu, Caina Xu, Pai Wang, Lei Guo, Xiuzhang Yan, Rui Zhou, Yixin Tang, Siyuan Wang, Jie Chen, Quan Wang, Huayu Tian.

  The five-year survival rate of patients with colorectal cancer (CRC) liver metastasis is less than 30 %, and chemotherapy resistance and metastatic microenvironment remodeling are the current treatment bottlenecks. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) form a "CRCs-CAFs crosstalk" with colorectal cancer cells (CRCs) by secreting dense extracellular matrix (ECM), free fatty acids (FFA), and pro-metastatic factors, driving a vicious cycle of drug resistance and metastasis. During liver metastasis, hepatic stellate cells (HSCs)-derived CAFs (HSC-CAFs) promote tumor metastasis by remodeling the pre-metastatic microenvironment. Based on clinical sample RNA sequencing and mouse single-cell sequencing to reveal ECM signal enrichment and CAFs activation characteristics, we innovatively constructed a nano-delivery system using hyaluronic acid-modified MIL-100 nanoparticles (OEMH NPs) co-loaded with oxaliplatin (OXA) and epigallocatechin gallate (EGCG). This system can target the CRCs-CAFs crosstalk through CD44 receptor: on the one hand, OEMH NPs can inhibit CAFs activation and reduce ECM deposition, improve drug penetration and down-regulate FFA metabolic reprogramming, reverse OXA resistance; on the other hand, OEMH NPs can block the transformation of HSCs to CAFs, down-regulate pro-metastatic factors such as VEGF/IL-11/ANG, induce vascular normalization, and reprogram the pre-metastatic microenvironment. This strategy can simultaneously achieve primary lesion drug sensitization and liver metastasis inhibition, providing a new paradigm for the treatment of advanced colorectal cancer to break through the traditional treatment dilemma through dual reprogramming of metabolism and microenvironment, and has significant clinical translation potential.

Keywords:  Cancer-associated fibroblasts; Chemoresistance; Colorectal cancer liver metastasis; Metal-organic framework; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bioactmat.2025.08.002
Nature. 2025 Aug 27.

Mechanical confinement governs phenotypic plasticity in melanoma.

Miranda V Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P Koche, Richard M White.

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.

DOI: https://doi.org/10.1038/s41586-025-09445-6
Sci Adv. 2025 Aug 22. 11(34): eadw6926

Liver regeneration-associated hepatocellular YAP1 activation prevents colorectal cancer liver metastasis through glutamine competition.

Qiang Yu, Mincheng Yu, Peiyi Xie, Lei Guo, Yufei Zhao, Wenxin Xu, Xian Li, Mengyuan Wu, Zihao Zhang, Zheng Chen, Yongsheng Xiao, Jian Zhou, Jia Fan, Mien-Chie Hung, Yongfeng Xu, Bo Zhang, Qinghai Ye, Hui Li.

The literature suggests that hepatocellular Yes-associated protein 1 (YAP1) signaling is activated following hepatectomy and that such activation can suppress the growth of metastatic liver tumors. The prognosis of a real-world cohort of 240 patients with colorectal cancer liver metastasis (CRLM) undergoing major and minor hepatectomy was compared after adjusting for confounding factors. To model CRLM, we induced liver metastasis in mice by transsplenically injecting MC38 cells. We found that patients with CRLM and mice undergoing major hepatectomy had better survival compared to those undergoing minor hepatectomy. Mechanistically, extensive hepatectomy activates hepatocellular YAP1 by regulating the epidermal growth factor receptor, altering glutamine metabolism-related gene expression and increasing liver glutamine consumption. This metabolic shift leads to glutamine scarcity in tumor cells, causing increased reactive oxygen species production, which promotes loss of YAP1 activity in tumor cells. Consequently, the production of the chemokine CXCL5 is suppressed, which inhibits myeloid-derived suppressor cell infiltration and enhancing the immunological function of CD8+ T cells.

DOI: https://doi.org/10.1126/sciadv.adw6926
EMBO Mol Med. 2025 Aug 26.

Understanding cancer cell plasticity: EMT, respecialisation, and therapeutic opportunities.

Anne-Pierre Morel, Maria Ouzounova.

DOI: https://doi.org/10.1038/s44321-025-00288-2
Free Radic Biol Med. 2025 Aug 25. pii: S0891-5849(25)00939-6. [Epub ahead of print]

Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer.

Allison Janak, Abhishek Jain, Rolando Garcia-Milian, Oladimeji Aladelokun, Xiaomei Ma, Philip B Paty, Sajid A Khan, Caroline H Johnson.

  Early-onset colorectal cancer (EO-CRC) occurring in individuals under age 50 is rapidly increasing globally, while the incidence of late-onset colorectal cancer (LO-CRC) has decreased over recent years. Previous studies have identified metabolites linked to CRC biology, however tumor-specific differences between EO-CRC and LO-CRC have not been explored. This study aimed to compare the tumor metabolome of EO-CRC and LO-CRC patients to reveal the unique biochemical state of EO-CRC. Mass spectrometry-based untargeted metabolomics was performed on tumor and patient-matched normal tissues from EO-CRC (n=53) and LO-CRC (n=314) patients to identify metabolites significantly altered in tumors (q≤0.05). Metabolite set enrichment analysis, metabolic pathway, and network analyses were performed, to identify the relationship between the altered metabolites and biological function. Analysis revealed 156 metabolites significantly altered between normal and tumor tissues. Homovanillic acid (HVA), a metabolite of dopamine, was uniquely downregulated in EO-CRC. Despite shared changes to HVA-metabolizing genes between EO- and LO-CRC the disruption in catecholamine metabolism may be specific to EO-CRC biology. Pathway and network analysis, supported by gene expression validation, showed that PD-L1 was uniquely decreased in EO-CRC suggesting immunosuppression. Additionally, phospholipid signaling was favored in EO-CRC, whereas LO-CRC tumors showed alterations to EGFR signaling and oxidative stress-related genes. In summary, this study reveals the metabolic nuances in tumor tissues from patients with EO-CRC and LO-CRC, indicating catecholamine metabolism, phospholipid signaling and immunosuppression in the biology of EO-CRC. These findings provide new insight into the metabolism of EO-CRCs that may inform new therapeutic strategies for this group of CRC patients.

Keywords:  early-onset colorectal cancer; tumor tissues; untargeted metabolomics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.052
J Adv Res. 2025 Aug 18. pii: S2090-1232(25)00643-5. [Epub ahead of print]

Multiple organs exhibit exacerbated cachexia in male mice with colon cancer than females.

Mara Barone, Martina Lunardi, Andrea David Re Cecconi, Federica Palo, Davide Olivari, Fulvia Cerruti, Paolo Cascio, Lorenzo Castagnoli, Martina Bigliardi, Laura Pasetto, Valentina Bonetto, Mariarita Galbiati, Angelo Poletti, Rosanna Piccirillo.

   INTRODUCTION: Cachexia is a lethal syndrome with massive muscle wasting that occurs in 60% of colon cancer patients. Several studies in humans and mice show that males are more prone than females to muscle atrophy caused by colorectal cancer. Understanding whether muscle atrophy precedes or follows other organ alterations may unravel the sex-specific drivers of cachexia.
OBJECTIVES: In two mouse models of colon cancer, we explored when cachexia affects multiple organs in both sexes and their sex development, if/how sex hormone may affect in vitro the inflammatory state of colon adenocarcinoma C26, HCT116 and human primary colorectal cancer cells and in vivo the progression of cachexia in C26-carriers.
METHODS: We compared tumor growth and cachexia-related responses in C26 males and females and C57BL/6J-ApcMin/+ mice of both sexes. C26, HCT116 and human primary colorectal cancer cells exposed to 17β-estradiol or the antagonist fulvestrant were analysed for Il-6 expression and secretion. β-estradiol 3-benzoate was given to C26 males.
RESULTS: In both models, cancer-bearing males display more/earlier muscle wasting than females. Muscle proteasome activity is enhanced only in cachectic males and only when they were sexually mature. During cachexia hypogonadism appears earlier in males than females of both models. Tumor-bearing females as long as they are "cycling" are more preserved from cachexia than males. Circulating levels of IL-6 increased more in C26 males than C26 females and spleens were bigger in C26 males also displaying more atrophic and inflamed muscles. 17β-estradiol halved the expression of Il-6 and abrogated the secretion of IL-6 from C26 cells, while fulvestrant surprisingly highly enhanced Il-6 expression, supporting an anti-inflammatory effect of estrogens directly on C26 cells. Similar data were obtained from human (primary) colorectal cancer cells. In vivo β-estradiol 3-benzoate prevented some signs of cachexia in C26 carriers.
CONCLUSION: Overall, we herein report a novel direct role of 17β-estradiol on colon cancer cells explaining why multiple tissues from males display more signs of cachexia than females.

Keywords:  Cancer cachexia; Colon cancer; Mouse models; Sex difference; Sex hormones

DOI:  https://doi.org/10.1016/j.jare.2025.08.028
Nat Cancer. 2025 Aug 21.

Colorectal cancer cells hijack a brain-gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth.

Ying Li, Hao Yu, Zi-Ming Li, Kai-Wen Yin, Shi-Yang Jin, Chao-Chao Chen, Ming-Shi Tan, Chuan-Jie Zhang, Xun-Hua Liu, Wei-Peng Li, Jian-Ming Yang, Ai-Jun Zhou, Xiang Zhang, En-De Ni, Meng-Ling Wang, Hui Mo, Chao Qin, Jian Hu, Shu-Ji Li, Tian-Ming Gao, Jian-Ming Li.

The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABAA receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression.

DOI: https://doi.org/10.1038/s43018-025-01033-x
Nat Commun. 2025 Aug 22. 16(1): 7834

Lymph nodes molecular subtypes unravel lymph nodes heterogeneity and clinical implications in colorectal cancer.

Xu Guan, Yueyang Zhang, Ruifang Sun, Guiyu Wang, Xiaoman Bi, Zhen Zhang, Likun Zan, Yongsheng Meng, Yunxiao Liu, Jinyuan Guo, Jian Ma, Jiale Li, Hanqing Hu, Yixun Zhang, Xin Zhang, Maoxi Liu, Bo Jiang, Haiyi Liu, Shuangmei Zou, Yanfeng Xi, Haitao Zhou, Wenqi Bai, Deng Wu, Xishan Wang.

Lymph nodes (LNs) play a pivotal role in colorectal cancer (CRC) progression and immunity, yet their molecular and functional diversity remains poorly understood. By analyzing 630 LNs and 88 primary tumors from 200 CRC patients across four independent cohorts using bulk and single-cell RNA sequencing, we identify four non-metastatic negative LNs (NLN) subtypes (NLN_C1-C4) exhibiting obviously different immune function and stromal expansion. NLN_C3/C4 are characterized by diminished T and B cell activity and fibroblast-driven fibrosis, with follicular dendritic cell loss contributing to B cell dysfunction. Immune checkpoint inhibitors partially reverse these effects, restoring FDC and B cell activity. LNs subtypes demonstrate heterogeneity across patients and within individuals, with higher NLN_C3/C4 proportions associated with advanced tumor stages, poorer survival, and recurrence. Here, we report LNs subtypes as critical manifestations of LN heterogeneity in CRC, providing a basis for improved clinical stratification and LN-targeted therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-63200-z
Nat Chem Biol. 2025 Aug 26.

Oncometabolite 5-IP7 inhibits inositol 5-phosphatase to license E-cadherin endocytosis.

Hongyun Zhang, Bobo Zhang, Yuebo Zhao, Yang Su, Yifan Peng, Xiaoli Yang, Hongming Zhao, Hongyu Liu, Jie Feng, Hongjing Pei, Wenyong Zhang, Niu Huang, Kai Jiang, Masatoshi Ito, Guizhen Liu, Nicolas Jork, Karen E Anderson, Li Zhao, Eiichiro Nagata, Henning J Jessen, Philip T Hawkins, Changzheng Du, Feng Rao.

E-cadherin downregulation is an epithelial-mesenchymal transition hallmark canonically attributed to transcriptional repression. Here we delineate a metabolite-driven endocytic route of E-cadherin downregulation in inflammation-associated colorectal cancer (CRC). Specifically, IP6 kinase-2 (IP6K2), a 5-diphosphoinositol pentakisphosphate (5-IP7) synthase upregulated in patients with CRC, is activated via a ROS-Src phosphorylation axis elicited by dextran sulfate sodium (DSS), generating 5-IP7 around adherens junction (AJ) to promote E-cadherin endocytosis and the transcriptional activities of β-catenin. Mechanistically, 5-IP7 inhibits inositol 5-phosphatases such as OCRL to promote PI(4,5)P2-mediated endocytic adaptor recruitment. Depleting 5-IP7 or overexpressing a 5-IP7 binding-deficient OCRL mutant confers resistance to DSS-elicited AJ disruption. Intestinal epithelium-specific IP6K2 deletion attenuates DSS-induced colitis/CRC, whereas an IP6K2 isoform-selective inhibitor protects wild-type but not IP6K2-/- mice against DSS insult. Thus, 5-IP7 is an oncometabolite whose stimulus-dependent synthesis relieves a PI(4,5)P2 dephosphorylation-based endocytic checkpoint, leading to AJ disassembly and protumorigenic β-catenin activation. Targeting IP6K2 could strengthen intestinal epithelial barrier against inflammation and cancer.

DOI: https://doi.org/10.1038/s41589-025-02005-z
Cell Death Discov. 2025 Aug 23. 11(1): 399

One-carbon metabolic pathway is a novel molecular signature for CD44-positive intestinal-type gastric cancer.

Seyeon Joo, Yoojin Bae, Bo Kyung Yoon, Yeonjin Je, Yuna Kim, Minki Kim, Su-Jin Shin, Sungsoon Fang, Jie-Hyun Kim.

Intratumoral heterogeneity (ITH), arising from various factors, plays a crucial role in diverse cancers, yet research on ITH remains in its early stages. To explore this phenomenon further, we conducted single-nuclei transcriptome profiling on patient-derived organoids (PDOs) from two histologically pure subtypes of gastric cancer. We identified differences in cancer stem cell marker expression among intestinal-type samples and their correlation with one-carbon (1C) metabolism. Notably, some gastric cancer samples, although histologically classified as intestinal-type, exhibited diffuse-like genetic characteristics. This finding suggests the potential for employing a 1C metabolism inhibition strategy as a therapeutic approach for these genetically diffuse-like gastric cancers. This study highlights the necessity of addressing ITH in PDO-based preclinical models and contributes valuable insights toward advancing precision medicine treatments for gastric cancer.

DOI: https://doi.org/10.1038/s41420-025-02704-5
Br J Cancer. 2025 Aug 20.

PROCC: a predictive score to identify KRAS wild type metastatic colorectal cancer patients who are likely to obtain survival benefit from panitumumab treatment.

Carlos María Galmarini, Rafael Zamora, Pablo Gómez Del Campo, José Del Castillo-Izquierdo, José Antonio De All, Juan Manuel Domínguez.

BACKGROUND: Practice guidelines recommend panitumumab with chemotherapy to treat KRAS wild-type (WT) metastatic colorectal cancer (mCRC) patients. However, not all patients respond to this therapy. We propose a score termed "PROCC" to identify likely panitumumab responders.
METHODS: The training (TRDS) and validation (VALDS) datasets included KRAS WT mCRC patients treated with panitumumab (P) plus chemotherapy (TRDS, FOLFOX4; VALDS, FOLFIRI). TRDS included 36 diverse features used to generate synthetic representations analyzed via machine learning (ML) to identify patient subgroups, which were correlated with PFS and OS. A multivariable logistic regression model identified independent predictors to develop a predictive score.
RESULTS: ML identified two subpopulations in TRDS: SP-A (n = 162) and SP-B (n = 298). Only SP-A patients under P/FOLFOX4 showed improved OS versus FOLFOX4 (HR 0.68; p = 0.04). CEA, ALP, LDH, and platelets at baseline were used to create a predictive score ("PROCC"). For TRDS, the score had an area under the curve of 0.81. PROCC ≥8.5 correlated with lower risks of progression (HR 0.67; p = 0.03) and death (HR 0.65; p = 0.04) for P/FOLFOX4 versus FOLFOX4. Validation in VALDS confirmed similar results with FOLFIRI.
CONCLUSIONS: Based on four baseline parameters, PROCC may guide the selection of KRAS WT mCRC patients most likely to benefit from panitumumab.

DOI: https://doi.org/10.1038/s41416-025-03157-4
Nat Genet. 2025 Aug 26.

ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L.

Weiran Feng, Erik Ladewig, Matthew Lange, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Elisa de Stanchina, Yu Chen, Brett S Carver, Christina S Leslie, Charles L Sawyers.

Despite the high prevalence of ERG transcription factor translocations in prostate cancer, the mechanism of tumorigenicity remains poorly understood. Using lineage tracing, we find the tumor-initiating activity of ERG resides in a subpopulation of murine basal cells that coexpress luminal genes (BasalLum) and not in the larger population of ERG+ luminal cells. Upon ERG activation, BasalLum cells give rise to highly proliferative intermediate (IM) cells with stem-like features that coexpress basal, luminal, hillock and club marker genes, before transitioning to Krt8+ luminal cells. Transcriptomic analysis of ERG+ human prostate cancers confirms the presence of rare ERG+ BasalLum cells, as well as IM cells whose presence is associated with a worse prognosis. Single-cell analysis revealed a chromatin state in ERG+ IM cells enriched for STAT3 transcription factor binding sites and elevated expression of the KMT2A/MLL1 and DOT1L, all three of which are essential for ERG-driven tumorigenicity in vivo. In addition to providing translational opportunities, this work illustrates how single-cell approaches combined with lineage tracing can identify cancer vulnerabilities not evident from bulk analysis.

DOI: https://doi.org/10.1038/s41588-025-02289-w
Nat Commun. 2025 Aug 26. 16(1): 7934

Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.

Xinzhu Li, Ying Zhu, Ting Li, Xinyi Tu, Shiyu Zhu, Lingzhi Wang, Fei Li, Chenglong Sun, Xin Li, Haiyi Zhao, Tang Tang, Qingce Zang, Ruiping Zhang, Zeper Abliz.

Organs collaborate to maintain metabolic homeostasis in mammals. Spatial metabolomics makes strides in profiling the metabolic landscape, yet can not directly inspect the metabolic crosstalk between tissues. Here, we introduce an approach to comprehensively trace the metabolic fate of 13C-nutrients within the body and present a robust computational tool, MSITracer, to deep-probe metabolic activity in a spatial manner. By discerning spatial distribution differences between isotopically labeled metabolites from ambient mass spectrometry imaging-based isotope tracing data, this approach empowers us to characterize fatty acid metabolic crosstalk between the liver and heart, as well as glutamine metabolic exchange across the kidney, liver, and brain. Moreover, we disclose that tumor burden significantly influences the host's hexosamine biosynthesis pathway, and that the glucose-derived glutamine released from the lung as a potential source for tumor glutamate synthesis. The developed approach facilitates the systematic characterization of metabolic activity in situ and the interpretation of tissue metabolic communications in living organisms.

DOI: https://doi.org/10.1038/s41467-025-63243-2
Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00656-2. [Epub ahead of print]

Endocytosis is essential for cysteine-deprivation-induced ferroptosis.

Xuesong Liu, Zechuan Zhao, Zhixuan Bian, Fahad A Benthani, Yingying Hu, Deguang Liang, Xuejun Jiang.

  Ferroptosis is a form of cell death caused by iron-dependent phospholipid peroxidation and subsequent membrane rupture. Autophagic degradation of the iron-storage protein ferritin promotes ferroptosis by increasing cytosolic bioactive iron, presumably explaining how lysosomal inhibitors suppress ferroptosis. Surprisingly, we found that lysosomal inhibitors suppress cysteine-deprivation-induced (CDI) ferroptosis, even in autophagy-defective cells, and subsequently discovered that clathrin-mediated endocytosis (CME) of transferrin is essential for CDI ferroptosis. Blocking lysosomal proteolytic activity failed to inhibit ferroptosis, whereas disrupting endosomal acidification and eliminating the endocytic protein AP2M1 both impeded ferroptosis. Conversely, replenishing cellular iron with ferric ammonium citrate, but not with transferrin, restored CDI ferroptosis in endocytosis-deficient cells. Unexpectedly, abolishing endosomal acidification, CME, and the associated increase in cellular labile iron could not prevent ferroptosis triggered by direct inhibition of the ferroptosis-suppressing enzyme glutathione peroxidase-4 (GPX4). Together, this study reveals the essential role of endocytosis, specifically for CDI ferroptosis.

Keywords:  AP2M1; GPX4; autophagy; cysteine deprivation; endocytosis; endosome; ferroptosis; iron; lysosome; transferrin

DOI:  https://doi.org/10.1016/j.molcel.2025.08.006
EMBO Rep. 2025 Aug 26.

STAT3 sustains tumorigenicity following mutant KRAS ablation.

Stephen D'Amico, Varvara Kirillov, Jingxuan Liu, Zhijuan Qiu, Xinyuan Lei, Hong Qin, Brian S Sheridan, Nancy C Reich.

  Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes and frequent relapse. Mechanisms of tumor resistance to KRAS inhibition remain poorly understood. We present evidence that STAT3 supports tumor growth following KRAS depletion. Using a conceptual framework of pancreatic ductal adenocarcinoma, we show that cancer cells that survive CRISPR-mediated ablation of mutant KRAS are dependent on STAT3 function to maintain tumorigenicity. Mechanistically, the combined loss of mutant KRAS and STAT3 disrupts a core transcriptional program of cancer cells critical to oncogenic competence. This in turn impairs tumor growth in mice and enhances immune rejection, leading to tumor clearance. We propose that the STAT3 transcriptional program operating in cancer cells enforces their malignant identity, rather than providing classical features of transformation, and shapes cancer persistence following KRAS inactivation. Our findings establish STAT3 as a critical enforcer of oncogenic identity in KRAS-ablated tumors, revealing a key vulnerability.

Keywords:  KRAS; Oncogene Dependence; Pancreatic Cancer; STAT3

DOI:  https://doi.org/10.1038/s44319-025-00563-w
Mol Cell. 2025 Aug 21. pii: S1097-2765(25)00644-6. [Epub ahead of print]85(16): 3009-3011

Lipoproteins: Friend and foe for ferroptosis?

Jin Gao, Yan Wang, Quan Chen.

A recent study in Nature reports a mechanism for cancer cells to defend against ferroptosis. Calhoon et al.1 showed that glycosaminoglycans on the cell surface promote lipoprotein uptake in cancer cells and deliver anti-ferroptotic metabolites such as α-tocopherol, providing ferroptosis resistance in tumor growth.

DOI: https://doi.org/10.1016/j.molcel.2025.07.021
ACS Biomater Sci Eng. 2025 Aug 26.

A Deep Learning Approach for Tracking Colorectal Cancer-Derived Extracellular Vesicles in Colon and Lung Models.

Giulia Chiabotto, Bianca Dumontel, Luca Zilli, Veronica Vighetto, Giorgia Savino, Francesca Alfieri, Michela Licciardello, Massimo Cedrino, Sabrina Arena, Chiara Tonda-Turo, Gianluca Ciardelli, Valentina Cauda.

  According to the International Agency for Research on Cancer and the World Health Organization, colorectal cancer (CRC) is the third most common cancer in the world and the main cause of gastrointestinal cancer-related deaths. Despite advances in therapeutic regimens, the incidence of metastatic CRC is increasing due to the development of resistance to conventional treatments. Metastases, particularly in the liver and lungs, represent the leading cause of death and poor prognosis in CRC patients. Recent evidence demonstrates that extracellular vesicles (EVs) are involved in communication between cancer cells and the surrounding environment. Understanding the potential mechanisms underlying EV-driven metastasis and tumor progression could facilitate the development of innovative strategies for early diagnosis and effective treatment of CRC metastasis. In this work, we developed a deep learning-based approach to track CRC-derived EVs in colon and lung models, enabling precise quantification of their uptake and trafficking in vitro. Moreover, we observed their tropism toward heterologous healthy cells in biologically relevant 3D models of colon and lung tissues, indicating the inherent role of CRC-EVs in metastatic niche formation and tumor initiation, raising their potential as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in CRC.

Keywords:  2D and 3D models; colorectal cancer; deep learning algorithm; extracellular vesicles; metastasis

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00380
Commun Biol. 2025 Aug 22. 8(1): 1261

3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer.

Sarah J Harmych, Thomas P Hasaka, Chelsie K Sievers, Seung Woo Kang, Marisol A Ramirez, Vivian Truong Jones, Zhiguo Zhao, Oleg Kovtun, Claudia C Wahoski, Qi Liu, Ken S Lau, Robert J Coffey, Joshua A Bauer, Bhuminder Singh.

Loss of polarity is a hallmark of cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype impacts prognosis and therapy outcomes, particularly in colorectal cancer (CRC). However, the mechanisms and drugs that impact EMT-related morphological changes are understudied, due to the complete failure of typical live/dead 2D high-throughput screens to capture morphology or the lack of robustness of 3D screens. We designed a high-throughput screen using 3D type I collagen cultures of CRC cells to assess morphological changes in colonies and identified several FDA-approved drugs that re-epithelialize CRC colonies. One of these drugs, azithromycin, increased colony circularity, enhanced E-cadherin membrane localization and ZO-1 localization to tight junctions, caused transcriptomic changes consistent with downregulation of EMT, and elevated sensitivity to the chemotherapeutic, irinotecan. A retrospective analysis of patient data demonstrated that the use of azithromycin in patients undergoing treatment for CRC with irinotecan had improved the 5 year survival compared to the chemotherapy alone. These results highlight the importance of morphological screens to identify novel drug candidates and synergistic mechanisms.

DOI: https://doi.org/10.1038/s42003-025-08699-0
Nat Cancer. 2025 Aug 25.

Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.

Zequn Lu, Can Chen, Heng Zhang, Bin Li, Yizhuo Liu, Jiayi Guo, Runying Xu, Ke Shi, Qianying Ma, Ming Zhang, Yimin Cai, Jinyu Huang, Hui Geng, Linyun Fan, Caibo Ning, Yanmin Li, Shuoni Chen, Wen Tian, Kexin Hu, Haijie Li, Xiaojun Yang, Chaoqun Huang, Yongchang Wei, Xu Zhu, Xiangpan Li, Zhen Xiong, Ming Cai, Xiaoyang Wang, Shaokai Zhang, Hongda Chen, Min Dai, Kun Chen, Mingjuan Jin, Meng Jin, Ying Zhu, Jianbo Tian, Xiaoping Miao.

Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10-13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development.

DOI: https://doi.org/10.1038/s43018-025-01031-z
J Exp Clin Cancer Res. 2025 Aug 22. 44(1): 247

Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.

Silvia Di Agostino, Davide La Padula, Vittoria Rago, Caterina Gabriele, Francesco Conforti, Elio Aprigliano, Lidia Urlandini, Elvira Parrotta, Danilo Lofaro, Francesca Vescio, Andrea Sacconi, Valeria Cernaro, Giuseppe Currò, Angela Alibrandi, Girolamo Ranieri, Valeria Zuccalà, Antonio Ieni, Marco Gaspari, Giovanni Cuda, Michele Ammendola, Vittorio Abbonante.

   BACKGROUND: The tumor microenvironment (TME) plays a pivotal role in the development and progression of colorectal cancer (CRC), yet the complex crosstalk among its components remains incompletely understood. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) have emerged as key regulators of CRC progression, but their specific contributions, particularly given their heterogeneity, are not fully elucidated. This study identifies podoplanin (PDPN), a transmembrane glycoprotein enriched in CAFs, as highly expressed in the CRC TME, in particular surrounding the tumor, and associated with macrophage infiltration and cancer progression.
METHODS: We performed mass spectrometry-based proteomic analysis on matched CRC and adjacent normal tissues from patients to identify altered signaling pathways and protein expression. The clinical relevance of PDPN expression was evaluated in CRC samples from two independent cohorts using immunohistochemistry and immunofluorescence analysis. Publicly available data from the Gene Expression Omnibus (GEO) database were analyzed to assess the association between PDPN expression and patient survival. Functional assays using direct and indirect co-culture systems investigated the influence of macrophage infiltration on stromal PDPN expression and its effect on colon adenocarcinoma cell growth.
RESULTS: PDPN expression was significantly elevated in the stroma of the colorectal tumor tissues compared to normal tissues and correlated with M2-like macrophage infiltration. High PDPN expression was associated with reduced relapse-free survival in CRC patients. Stromal cells pre-conditioned with M2-like macrophages upregulated PDPN and more effectively supported the growth of three colon adenocarcinoma cell lines. PDPN depletion impaired the ability of stromal cells to promote tumor cell proliferation. Mechanistically, M2-like macrophage pre-conditioning induced a TGF-β1-dependent increase in YAP/TAZ nuclear localization, RhoA/ROCK/myosin-driven cytoskeletal contractility, and extracellular matrix (ECM) production in stromal cells. Inhibition of TGF-β1 signaling or ROCK activity reduced stromal support for cancer cell growth.
CONCLUSION: This study reveals a novel mechanism by which the TME facilitates CRC progression and highlights PDPN as a potential prognostic biomarker and therapeutic target in CRC.

Keywords:  Cancer associated fibroblasts; Colorectal cancer; Proteomic; Transforming growth factor beta; Tumor associated macrophages; Tumor microenvironment; YAP/TAZ

DOI:  https://doi.org/10.1186/s13046-025-03496-3
Oncogene. 2025 Aug 24.

GABAergic signaling contributes to tumor cell invasion and poor overall survival in colorectal cancer.

Carly Strelez, Francesca Battaglin, Rachel Perez, Yan Yang, Christopher Cherry, Joshua Millstein, Ah Young Yoon, John S Chlystek, Ethan Canfield, Bethany Haliday, Curran Shah, Kimya Ghaffarian, Shivani Soni, Hannah Jiang, Roy Lau, Aaron Schatz, Yuyuan Zhou, Daniel Mulkerin, Fang-Shu Ou, Alan P Venook, Federico Innocenti, Josh Neman, Jonathan E Katz, Heinz-Josef Lenz, Shannon M Mumenthaler.

Alterations in neurotransmitter signaling can influence colorectal cancer (CRC). In a large, randomized Phase III clinical trial (CALGB/SWOG 80405) involving patients with metastatic CRC, high expression of gamma-aminobutyric acid (GABA) pathway gene GAD1 and low expression of ABAT, indicative of a GABAergic environment, were associated with worse progression-free survival and overall survival outcomes. A metastasis map of human cancer cell lines (MetMap) and functional studies using a microfluidic tumor-on-chip platform demonstrated that high GAD1 expression correlates with increased metastatic potential. Knockdown and pharmacological inhibition of GAD1 reduced tumor invasion, while exogenous GABA promoted invasion. Tumor-derived GABA was elevated in Ras-altered tumors. Furthermore, analysis of publicly available data confirmed that higher GAD1 expression is associated with worse outcomes in Ras-mutant tumors. These findings establish a role for GABA signaling in tumor invasiveness, particularly in Ras-altered CRC. This study demonstrates using clinical data to inform new discoveries and highlights the need for advanced preclinical model systems that more accurately reflect human physiology to explore these findings.

DOI: https://doi.org/10.1038/s41388-025-03546-2