bims-instec 2025-07-13 papers

bims-instec

Biomed News

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

Issue of 2025–07–13
twenty papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Colon cancer cells evade drug action by enhancing drug metabolism.
Abnormal β-Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer.
PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling.
Fatty acid binding protein 1 (FABP1) depletion promotes an oxidative metabolic shift in Caco-2 colorectal cancer cells.
Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
Elacridar improves sunitinib efficacy in colorectal cancer models.
Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cells.
CDX2 loss in colorectal cancer cells is associated with invasive properties and tumor budding.
Regulation of revival stem cell differentiation by CREPT/RPRD1B during intestinal regeneration.
BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer.
The multifaceted contributions of cancer-associated fibroblasts to drug resistance in primary and metastatic tumors.
Mathematical modelling of cancer cell evolution and plasticity.
Deep crypt secretory cells shape region-specific mucin glycosylation patterns in the mouse colon.
AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer.
Nutrients activate distinct patterns of small-intestinal enteric neurons.
P300-dependent acetylation of the FOXQ1 complex activates super-enhancers to promote colorectal cancer proliferation and metastasis.
Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP.
Decoding the genomic landscape of early-onset colorectal cancer: the next chapter in precision oncology.
PLIN2 promotes colorectal cancer progression through CD36-mediated epithelial-mesenchymal transition.
High Throughput Screening Identifies Small Molecules that Synergize with MRTX1133 Against Acquired Resistant KRAS G12D Mutated CRC.

Oncogene. 2025 Jul 10.

Colon cancer cells evade drug action by enhancing drug metabolism.

Bojie Cong, Teena Thakur, Alejandro Huerta Uribe, Evangelia Stamou, Sindhura Gopinath, Owen Sansom, Oliver Maddocks, Ross Cagan.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. One key reason is the lack of durable therapies that target KRAS-dependent disease, which represents approximately 40% of CRC cases. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway-a toxin clearance pathway that impacts most drugs-as upregulated in trametinib-resistant RAS/APC/P53 ("RAP") tumours compared to trametinib-sensitive RasG12V single mutant tumours. Genetic inhibition of different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib; conversely, elevating glucuronidation pathway activity was sufficient to direct trametinib resistance in RasG12V animals. Mechanistically, pairing oncogenic RAS with hyperactive WNT activity strongly elevated PI3K/AKT/GLUT signalling, which in turn directed elevated glucose uptake and glucuronidation; our data also implicate the pentose phosphate pathway in this process. We provide evidence that this mechanism of trametinib resistance is conserved in a KRAS/APC/TP53 mouse CRC tumour organoid model. Finally, we identify two clinically accessible approaches to inhibiting drug glucuronidation: (i) blocking an initial HDAC1-mediated deacetylation step of trametinib with the FDA-approved drug vorinostat; (ii) reducing blood glucose by the alpha-glucosidase inhibitor acarbose. Overall, our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC and provides a practical path towards abrogating drug resistance in CRC tumours.

DOI: https://doi.org/10.1038/s41388-025-03472-3
Adv Sci (Weinh). 2025 Jul 11. e02402

Abnormal β-Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer.

Chuman Lin, Zhiyang Li, Xiaotong Zhu, Wanbing Zhou, Xiansheng Lu, Jiali Zheng, Jie Lin.

  The abnormal arginine metabolism is characteristic of tumor cell metabolism in colorectal cancer (CRC). However, the mechanisms underlying arginine metabolic reprogramming and how altered metabolism in turn enhances CRC tumorigenicity are poorly understood. Protein post-translational modifications (PTMs) are crucial for regulating protein function, activity, and interactions. Here, the study reports that arginine levels are elevated in CRC, accompanied by the high expression of arginase-1 (ARG1) but low levels of ARG1 β-hydroxybutyrylation (Kbhb) and its oncogenic role in CRC in a catalytic-activity-independent manner. Mechanistically, low-level ARG1-Kbhb-induced arginine metabolic reprogramming by decreasing the interaction of ARG1 with SLC3A2 in CRC cells inhibits the efflux of arginine, thereby increasing intracellular arginine levels to promote tumorigenicity. P300 is identified as the "writer" of Kbhb. Inducing ARG1-Kbhb at the Lys313 residue by β-hydroxybutyrate (BHB) promotes the interaction of ARG1 with SLC3A2, resulting in the efflux of arginine in CRC cells. Together, these findings reveal valuable insights into arginine metabolism reprogramming involving the ARG1-Kbhb/P300/SLC3A2 signaling axis, thereby bridging the connection between metabolic reprogramming and PTMs, which may shed light on the therapeutic potential of combining BHB with ARG1 inhibitor through the conventional enzymatic role and nonenzymatic metabolic function of ARG1 for CRC.

Keywords:  ARG1; arginine metabolism reprogramming; colorectal cancer; β‐hydroxybutyrylation

DOI:  https://doi.org/10.1002/advs.202502402
J Exp Clin Cancer Res. 2025 Jul 10. 44(1): 198

PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling.

Caterina Mancini, Giulia Lori, Gianluca Mattei, Marta Iozzo, Dayana Desideri, Fabio Cianchi, Laura Fortuna, Federico Passagnoli, Daniela Massi, Filippo Ugolini, Luca Messerini, Salvatore Piscuoglio, Antonio Pezone, Francesca Magherini, Alessio Biagioni, Tiziano Lottini, Demetra Zambardino, Giuseppina Ivana Truglio, Elena Petricci, Alberto Magi, Annarosa Arcangeli, Luisa Maresca, Barbara Stecca, Erica Pranzini, Maria Letizia Taddei.

   BACKGROUND: Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different "non-enzymatic roles" for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC.
METHODS: Overexpression and gene silencing approaches have been used to modulate PHGDH expression in human CRC cell lines to investigate the role of this enzyme in 5-FU cellular response. Identified mechanisms have been validated in selected 5-FU resistant cell lines, CRC patients-derived tumor tissue samples, and patients-derived 3D organoids. Transcriptomic analysis was performed on wild-type and PHGDH-silenced cell lines, allowing the identification of pathways responsible for PHGDH-mediated 5-FU resistance. The relevance of identified genes was validated in vitro and in vivo in a CRC xenograft model.
RESULTS: PHGDH expression is highly variable among CRC tissues and patient-derived 3D organoids. A retrospective analysis of CRC patients highlighted a correlation between PHGDH expression and therapy response. Coherently, the modulation of PHGDH expression by gene silencing/overexpression affects 5-FU sensitivity in CRC cell lines. Transcriptomic analysis on CRC cell lines stably silenced for PHGDH evidenced down regulation in Hedgehog (HH) pathway. Accordingly, in vitro and in vivo studies demonstrated that the combined treatment of 5-FU and HH pathway inhibitors strongly hinders CRC cell survival and tumor growth in CRC xenograft models.
CONCLUSIONS: PHGDH sustains 5-FU resistance in CRC by mediating the upregulation of the HH signaling; targeting the here identified PHGDH-HH axis increases 5-FU susceptibility in different CRC models suggesting the 5-FU/HH-inhibitors combinatorial therapeutic strategy as a valid approach to counteract drug resistance in CRC.

Keywords:  5-Fluorouracil; Chemo-resistance; Colorectal cancer; Hedgehog signaling; Phosphoglycerate dehydrogenase; Serine; Stemness

DOI:  https://doi.org/10.1186/s13046-025-03447-y
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jul 08. pii: S1388-1981(25)00069-1. [Epub ahead of print] 159661

Fatty acid binding protein 1 (FABP1) depletion promotes an oxidative metabolic shift in Caco-2 colorectal cancer cells.

Delfina Lucía Borús, Giorgia Zadra, Daniel Minsky, María Lucía Costa, Betina Córsico, Judith Storch, Natalia Scaglia.

  Lipid metabolism reprogramming is a well-established hallmark of many cancer types, including colorectal cancer (CRC). Nevertheless, a clear understanding on how fatty acid (FA) metabolism is fine-tuned during CRC development and progression is still missing. Given that CRC is the second leading cause of cancer-related death, addressing these critical aspects may provide the rationale for new therapeutic approaches and early biomarker identification. Fatty acid binding protein 1 (FABP1) is a small protein that binds FA and other lipophilic compounds, acting as a lipid transporter in the intestine. Little is currently known about the function of FABP1 in CRC. Here we show that the knockdown of FABP1 in CRC cells impairs de novo FA and cholesterol synthesis, specifically, via altering the transcriptional regulation of lipid metabolism genes. FABP1 depletion suppresses the expression of FA and cholesterol synthesis-associated genes while promoting that of FA oxidation genes and mitochondrial oxidative pathways. The latter is associated with increased oxygen consumption rate and activation of the energy sensor 5' AMP-activated kinase (AMPK). Taken together, our results show that FABP1 orchestrates the balance between FA synthesis and oxidation, most likely to prevent the cytotoxic effects of circulating unbound free fatty acids. Thus, targeting FABP1 function may represent a potential therapeutic strategy in advanced CRC.

Keywords:  Colorectal cancer; FABP1; Fatty acid biosynthesis; Fatty acid β-oxidation; Lipogenesis; Oxidative metabolism

DOI:  https://doi.org/10.1016/j.bbalip.2025.159661
Gastroenterology. 2025 Jul 07. pii: S0016-5085(25)05732-4. [Epub ahead of print]

Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

Pornlada Likasitwatanakul, Zhixin Li, Paul Doan, Sandor Spisak, Akhouri Kishore Raghawan, Qi Liu, Priscilla Liow, Sunwoo Lee, David Chen, Pratyusha Bala, Pranshu Sahgal, Daulet Aitymbayev, Jennifer S Thalappillil, Malvina Papanastasiou, William Hawkins, Steven A Carr, Haeseong Park, James M Cleary, Jun Qi, Nilay S Sethi.

   BACKGROUND AND AIMS: Aberrant epigenetic programs that suppress differentiation and enhance plasticity drive colorectal cancer (CRC), yet the molecular determinants underlying these processes remain elusive. We aimed to identify and characterize epigenetic regulators of CRC differentiation, uncovering mechanisms that reprogram cancer cell states.
METHODS: A small molecule library targeting epigenetic regulators was screened using an endogenous dual reporter system. We evaluated lead compounds in mouse and human CRC models via histopathology, cellular assays, epigenetic studies, mass-spectrometry-based histone modification profiling, and single cell RNA-sequencing. Integrative analyses of drug-induced chromatin dynamics, gene expression, target engagement, and histone marks elucidated molecular mechanisms. Focused genetic screens were conducted to identify regulators of HDAC1/2-mediated differentiation.
RESULTS: We found that inhibition of histone deacetylase (HDAC) 1/2 catalytic domain promotes CRC differentiation and suppresses tumor growth. Unbiased profiling of histone modifications identified H3K27ac and H3K9ac as critical regulatory marks, with genome-wide analyses demonstrating their enrichment at HDAC1/2-bound regions associated with open chromatin and upregulated differentiation genes. Disrupting H3K27ac by targeted degradation of acetyltransferase EP300 reversed the differentiation phenotype induced by HDAC1/2 inhibition in a patient-derived CRC organoid. Genetic screens revealed that DAPK3 contributes to H3K27ac-mediated CRC differentiation induced by HDAC1/2 inhibition.
CONCLUSIONS: Our findings establish histone acetylation as a chemically targetable mechanism governing CRC cell fate and demonstrate that epigenetic reprogramming can be leveraged as a therapeutic strategy. By identifying HDAC1/2 inhibition as a driver of differentiation and revealing H3K27ac as a key regulatory mark, this study provides a framework for targeting chromatin-modifying enzymes to counteract CRC plasticity and improve treatment outcomes.

Keywords:  colorectal cancer; epigenetic regulation; intestinal differentiation; stem cell

DOI:  https://doi.org/10.1053/j.gastro.2025.07.003
Eur J Pharm Sci. 2025 Jul 08. pii: S0928-0987(25)00193-9. [Epub ahead of print] 107194

Elacridar improves sunitinib efficacy in colorectal cancer models.

Dennis Poel, Kirti K Iyer, Bob van Gasteren, Beau B C Dagniaux, Erik van den Hombergh, Daniele V F Tauriello, Henk M W Verheul, Nielka P van Erp.

  To improve treatment outcome for unresectable metastatic colorectal cancer (mCRC), many small molecule kinase inhibitors (KIs) have been tested. Most fail in early-phase clinical trials due to intrinsic resistance. As ATP Binding Cassette transporters are known to cause treatment resistance in mCRC, as well as to obtain higher intracellular drug concentrations, we evaluated whether inhibition of these transporters could potentiate KI efficacy. In patient-derived tumour organoids (PDTOs) from mCRC biopsies, preincubation with potent transporter inhibitor elacridar significantly improved sunitinib efficacy. Contrasting expectations, this was accompanied by reduced intracellular sunitinib accumulation. Mechanistically, confocal fluorescence imaging revealed reduced lysosomal sequestration of sunitinib in cells preincubated with elacridar. Storage of drugs-that are lysosomotropic and substrates of ABC-transporters-in subcellular compartments reduces the active pool and potentially contributes to intrinsic drug resistance in mCRC. Combination strategies that target ABC-transporters or lysosomes might be considered to potentiate drug efficacy.

Keywords:  ABC-transporters; Kinase inhibitors; metastatic colorectal cancer; patient-derived tumour organoids; preclinical pharmacokinetics

DOI:  https://doi.org/10.1016/j.ejps.2025.107194
bioRxiv. 2025 Jul 05. pii: 2025.07.01.662602. [Epub ahead of print]

Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cells.

Varun Ponnusamy, Deahzana R Randall, Zheng Hong Lee, Nupur K Das, Liang Zhao, Kathryn Buscher, Sumeet Solanki, Adam R Renslo, Peggy P Hsu, Yatrik M Shah.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the oncogenic benefits of elevated iron must be counterbalanced by its potential to catalyze oxidative damage via reactive oxygen species generated from labile, redox-active iron. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. This process is tightly controlled by the selenoenzyme glutathione peroxidase 4 (GPX4), which reduces lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined. To examine this, we supplemented CRC cells with exogenous iron following pharmacologic induction of ferroptosis. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, whether ferroptosis is accompanied by dynamic changes in the LIP, and if such changes are mechanistically required for its potentiation, was unknown. To further characterize this response, we profiled the expression of iron regulatory genes under ferroptotic conditions and observed no change in transcriptional response in iron homeostasis genes. When using a fluorescent probe for labile iron, we found that the LIP did not measurably increase during ferroptosis induction. These findings suggest that the LIP itself does not expand after the initiation of ferroptosis to become the primary driver of ferroptotic potentiation.

DOI: https://doi.org/10.1101/2025.07.01.662602
Sci Rep. 2025 Jul 06. 15(1): 24113

CDX2 loss in colorectal cancer cells is associated with invasive properties and tumor budding.

Nils Bodmer, Kristin Uth, Rina Mehmeti, Cansaran Saygili Demir, Deborah Stroka, Nassim Ghaffari-Tabrizi-Wizsy, Alessandro Lugli, Olivier de Wever, Inti Zlobec, Mario P Tschan.

  In colorectal cancer (CRC), tumor buds (TB) are observed histologically as single tumor cell or small tumor cell clusters located mainly at the advancing tumor edge. TB are a marker of poor prognosis and correlate with metastatic disease in CRC patients. They often lack expression of CDX2 and overexpress markers involved in epithelial-mesenchymal transition (EMT). We evaluated the function of CDX2 in CRC proliferation and migration using CRISPR/Cas9 technology and demonstrated a possible link to tumor dissociation and tumor budding. Knocking out CDX2 in CRC cell lines significantly increased migration. Importantly, the observed phenotypes could be rescued by re-expressing CDX2 and by specific CRISPR synergistic activation mediator (SAM) of endogenous CDX2 in CDX2 low expressing CRC cell lines. Multiplex immunofluorescence (mIF) analysis of primary tumor regions compared to TB in a CDX2-positive CRC patient sample as well as patient derived xenografts (PDX) revealed significantly lower CDX2 expression and correlating E-cadherin levels in TB compared to primary tumor regions, in both models. Accordingly, increased invasiveness of CRC CDX2 knockout cells was seen in ex ovo xenografts. Taken together, our results provide further insight into the function of CDX2 in preventing CRC cell migration, tumor budding and tumor aggressiveness.

Keywords:  CDX2; Cell migration; Colorectal cancer; EMT; Tumor budding

DOI:  https://doi.org/10.1038/s41598-025-07278-x
Cell Biosci. 2025 Jul 07. 15(1): 98

Regulation of revival stem cell differentiation by CREPT/RPRD1B during intestinal regeneration.

Tingwei Lan, Mengdi Li, Xiaolin Duan, Huihui Jia, Yajun Cao, Yinyin Wang, Fangli Ren, Jianqiu Sheng, Junfeng Xu, Zhijie Chang.

  Revival stem cells (revSCs) defined by transient induction of clusterin (CLU) expression rapidly expand and differentiate into multiple IEC lineages during intestinal regeneration. Although revSC induction is well-studied, the mechanisms governing their differentiation remain unclear. In this study, we demonstrate that CREPT/RPRD1B, a protein highly expressed in tumors and essential for crypt-base columnar cell (CBC) maintenance, was required for revSC differentiation during intestinal regeneration. Using Villin-Cre-mediated CREPT knockout (Vil-CREPTKO) mice, we found that CREPT deletion leads to regeneration failure following irradiation-induced damage. Interestingly, revSCs were remarkably accumulated, but enterocytes were decreased in Vil-CREPTKO mice. Our single-cell transcriptome analyses demonstrated that CREPT deletion impaired the stem potential of revSCs and inhibited their differentiation into enterocytes and goblet cells. Lineage tracing experiments confirmed the reduced regenerative capacity of CREPT-deficient revSCs in vivo. Together, our findings identified CREPT as an important regulator of revSC differentiation during intestinal regeneration.

Keywords:  CREPT/RPRD1B; Differentiation; Intestinal regeneration; Intestinal stem cell; Revival stem cell

DOI:  https://doi.org/10.1186/s13578-025-01434-6
Mol Cancer Ther. 2025 Jul 10.

BCL-2 family inhibition enhances MTORC1/2 inhibition in PIK3CA mutant colorectal cancer.

Rebecca A DeStefanis, Alexa E Schmitz, Alyssa K Steimle, Susan N Payne, Gioia C Sha, Autumn M Olson, Alec Cornelio, Anna E L Lippert, Sean G Kraus, Katherine A Johnson, Peter F Favreau, Amani Gillette, Christopher Babiarz, Devon Miller, Carley M Sprackling, Cheri A Pasch, Stephanie Pritzl, Dana R Van De Hey, Demetra P Korkos, Tyler M Foley, Alexander E Yueh, Aurora L J X Greane, Linda Clipson, Melissa C Skala, Dustin A Deming.

Targeting PIK3CA mutant colorectal cancers (CRCs) with precision medicine strategies is of great clinical interest. However, resistance to single agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of MTORC1/2 is necessary to induce a response in PIK3CA mutant CRCs. The PI3K/MTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA mutant solid tumors as part of the NCI MATCH trial. Here we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA mutant CRCs. Using a novel high-throughput drug screen method in Apc and Pik3ca mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo CRC models, navitoclax enhanced PI3K/MTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for MTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA mutant CRCs.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-1096
Drug Resist Updat. 2025 Jul 01. pii: S1368-7646(25)00076-7. [Epub ahead of print]82 101273

The multifaceted contributions of cancer-associated fibroblasts to drug resistance in primary and metastatic tumors.

Xinhao Zhang, Yuhang Wang, Wenming Cui, Danyang Li, Junmin Song, Zhen Li, Ying Liu, Shuaixi Yang.

  Drug resistance remains a formidable barrier in modern oncology, undermining the efficacy of the current therapeutic regimens. As pivotal stromal constituents within tumor ecosystems, cancer-associated fibroblasts (CAFs) have emerged as critical mediators of treatment resistance through multifaceted mechanisms. In this review, we summarize the historical progression of research on CAFs and drug resistance, and highlight the recent discoveries related to CAF biomarkers and their functions associated with drug resistance. Furthermore, we discuss the relationship between CAF heterogeneity, secretion, autophagy, and senescence and their contributions to the evolution of drug resistance. Additionally, we provide a detailed explanation of how CAFs contribute to the development of drug resistance in primary tumors, including mechanisms such as immune suppression and evasion, promotion of tumor stemness, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. We also explored the role of CAFs in metastatic tumors and their association with drug resistance at various metastatic sites, including lymph nodes, brain, lungs, peritoneum, bone, and liver. Finally, we summarize the advancements in clinical trials targeting CAFs, the emerging research on potential therapeutic targets, and anticipating future trends in this area.

Keywords:  Cancer-associated fibroblasts; Drug resistance; Metastatic tumor; Pre-metastatic niche; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.drup.2025.101273
Curr Opin Cell Biol. 2025 Jul 09. pii: S0955-0674(25)00096-1. [Epub ahead of print]95 102558

Mathematical modelling of cancer cell evolution and plasticity.

Chloé Colson, Frederick Jh Whiting, Ann-Marie Baker, Trevor A Graham.

In this review, we argue that mathematical modelling is an essential tool for understanding cancer cell evolution and phenotypic plasticity. We show that mathematical models enable us to reconstruct time-dependent tumour evolutionary dynamics from temporally-restricted biological data. In their ability to capture complex biological processes, they also serve as a means for in silico experimentation. In particular, they allow us to investigate different biological hypotheses and generate experimentally-testable predictions about underlying mechanisms of phenotype evolution and treatment resistance. Finally, mathematical models can reveal which biological data is informative, and, in combination with our understanding of which biological hypotheses need to be tested, they can guide experimental and clinical trial design.

DOI: https://doi.org/10.1016/j.ceb.2025.102558
PLoS One. 2025 ;20(7): e0326157

Deep crypt secretory cells shape region-specific mucin glycosylation patterns in the mouse colon.

Daisuke Sugahara, Hayato Kawakami, Yoshihiro Akimoto.

The colonic mucin layer, comprising highly glycosylated mucin proteins, is crucial for maintaining colonic health. Its region-specific glycosylation patterns are indispensable for adapting to distinct physiological and microbial environments along the colon, thus ensuring appropriate mucin layer function. However, the mechanisms underlying this region-specific glycosylation remain unknown. Here, using fluorescence-based immunohistological analyses of the colon from experimental mice, we demonstrated that along with contribution of goblet cells, as conventionally believed, mucin glycosylation involves deep crypt secretory (DCS) cells, a specialized mucin-producing cell population in the colon. Based on cKit/CD117 as a DCS cell marker, DCS and goblet cells are inversely distributed along the mouse colon: DCS cells predominate proximally, constituting nearly 70% of mucin-producing cells, whereas goblet cells are more abundant distally, indicating a dynamic shift in the predominant mucin-producing cell population along the colon. Immunofluorescence staining revealed that DCS cells produce distinctive mucin-glycans, including those with the Core3-glycan motif that exhibit region-specific distributions in the mucin layer. We found that the gradient distribution of DCS cells predominantly shapes their region-specific distribution, whereas the inverse distribution of goblet cells corresponds to the distal distribution of sulfated and sialylated glycans. Furthermore, the in situ Proximity Ligation Assay for specifically detecting Muc2 with distinct glycosylation, revealed that DCS and goblet cells produce different types of α1,2-fucosylated glycans on Muc2, indicating that the shift in the predominant mucin-producing cells drives region-specific α1,2-fucosylation on Muc2 across colonic regions. Although DCS cells are implicated in supporting the stem cell niche, their involvement in mucin production was unclear. We highlight the critical role of DCS cells in establishing regional glycosylation patterns. Our findings provide new insights into the cellular basis of mucin glycosylation, as well as their potential impact on colonic health and disease susceptibility in specific colonic regions.

DOI: https://doi.org/10.1371/journal.pone.0326157
Cancer Res. 2025 Jul 10. OF1-OF12

AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer.

Daniela Conticelli, Marco Volante, Filippo Pietrantonio, Claudia Orrù, Martina Olivero, Alessia Nottegar, Felice Borghi, Gian L Baiocchi, Giovanni Crotti, Uberto Fumagalli Romario, Giovanni De Manzoni, Rossella Reddavid, Roberta Porporato, Dinçer Kılıç, Rebecca Ghione, Erika Calabrò, Russell Petty, Simona Corso, Silvia Giordano, Cristina Migliore.

EGFR is a potential therapeutic target in gastroesophageal cancer. However, negative results from several phase II/III clinical trials have hindered the approval of EGFR inhibitors for treating gastroesophageal adenocarcinoma. Preclinical and clinical results have shown that EGFR targeting is effective in patients with gastroesophageal adenocarcinoma harboring EGFR amplification. Retrospective analyses also suggest that a subset of patients with gastroesophageal adenocarcinoma lacking EGFR amplification may benefit from the treatment, thus underscoring the need to identify reliable predictive biomarkers of response. Through the screening of 27 gastroesophageal adenocarcinoma primary cancer cell lines and 10 patient-derived xenograft models, we identified a subset of gastroesophageal adenocarcinoma lacking EGFR quantitative alterations but sensitive to EGFR targeting. Molecular characterization of the sensitive models revealed overexpression of the EGFR ligand amphiregulin (AREG) or epiregulin (EREG). Post hoc analysis of patients on the Cancer Esophagus Gefitinib trial treated with the EGFR inhibitor gefitinib demonstrated a significant correlation between overall survival and AREG/EREG expression level. No predictive power of EGFR ligand expression was observed in the presence of KRAS mutations. In conclusion, this study proposes the existence of a subgroup of patients with gastroesophageal adenocarcinoma with susceptibility to EGFR inhibition driven by overexpression of the EGFR ligands AREG and EREG.
SIGNIFICANCE: Elevated levels of AREG or EREG in gastroesophageal cancer confers sensitivity to EGFR inhibition, providing a low-toxicity treatment option for the subpopulation of patients overexpressing the EGFR ligands.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0073
Nature. 2025 Jul 09.

Nutrients activate distinct patterns of small-intestinal enteric neurons.

Candice Fung, Tom Venneman, Amy M Holland, Tobie Martens, Milvia I Alata, Marlene M Hao, Ceyhun Alar, Yuuki Obata, Jan Tack, Alejandro Sifrim, Vassilis Pachnis, Werend Boesmans, Pieter Vanden Berghe.

The ability to detect and respond appropriately to ingested nutrients is essential for an organism's survival and to ensure its metabolic demands are met. Nutrient signals from the gut lumen trigger local intestinal reflexes in the enteric nervous system (ENS) to facilitate digestion and absorption1-4, but the precise cellular pathways that are involved in the initial neuronal sensory process remain unclear. The extent to which the ENS is capable of discerning different luminal chemicals is also unknown. Here we use calcium imaging to identify specific enteric pathways that are activated in response to luminal nutrients applied to mouse jejunum. Notably, we show that different nutrients activate neurochemically defined ensembles of myenteric and submucosal neurons. Furthermore, we find that enteric neurons are not directly sensitive to nutrients but detect different luminal chemicals through the epithelium, mainly via a serotonin signalling pathway. Finally, our data reveal a spatial distribution of luminal information along the radial axis of the intestine, whereby some signals that originate from the villus epithelium are transmitted first to the myenteric plexus, and then back to the submucosal plexus, which is closer to the lumen.

DOI: https://doi.org/10.1038/s41586-025-09228-z
Commun Biol. 2025 Jul 07. 8(1): 1016

P300-dependent acetylation of the FOXQ1 complex activates super-enhancers to promote colorectal cancer proliferation and metastasis.

Wen-Dong Yang, Zhi-Heng Zhang, Man-Yi Zhao, Ke Shao, Yan-Feng Ma, Qi Shen, Meng-Ru Lu, Zhi-Ying Shao, Jia-Yu Xu, Meng-Han Cao, Seng Meng, Su-Fang Chu, Hong-Mei Yong, Jin Ding, Jin Bai.

The FOX transcription factor family plays a pivotal role in the malignant progression of tumors. We propose a hypothesis that FOXQ1 recruits p300 and BRD4 to super-enhancer regions. Our findings indicate that p300 acetylates Lys190 of FOXQ1, resulting in its recognition and binding by BRD4. Subsequently, BRD4 recruits RNA-Pol II to form a "FOXQ1-p300-BRD4-RNA Pol II" complex, which then binds to the super-enhancers of target genes. Meanwhile, acetylation at Lys190 of FOXQ1 directly enhances its binding affinity to super-enhancers. Consequently, more target oncogenes can be transcribed to promote CRC proliferation and metastasis. Our results suggest that FOXQ1 acts as a key regulator of super-enhancers, providing insights into its role in CRC and highlighting its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s42003-025-08430-z
bioRxiv. 2025 Jul 02. pii: 2025.06.30.662346. [Epub ahead of print]

Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP.

Bohdana M Rovenko, Kari Moisio, Cornelia Biehler, Mykhailo Girych, Atte Hallasaari, Onur Deniz, Sarah Bluhm, Arto Viitanen, Krista Kokki, Gaia Fabris, Yi Yang, Valentin Cracan, Irene Miguel-Aliaga, Ville Hietakangas.

Enteroendocrine (EE) cells monitor the intestinal nutrient composition and consequently control organismal physiology through hormonal signaling. In addition to the immediate effects on hormone secretion, nutrients influence EE cell abundance by affecting the determination and maintenance of cell fate. EE cells are known to import and respond to dietary sugars, but how the sugar-induced changes in the intracellular metabolic state are sensed to control the immediate and long-term responses of EE cells, remains poorly understood. We report that the NADH binding transcriptional cofactor C-terminal binding protein (CtBP) acts at the interface between nutrient sensing and fate regulation of Drosophila larval EE cells, thus controlling organismal energy metabolism and survival on a high sugar diet. CtBP dimerization in EE cells is regulated through the redox balance of nicotinamide cofactors controlled by glycolysis and pentose phosphate pathway, allowing EE cells sense their internal metabolic state in response to sugar catabolism. CtBP interacts with the EE cell fate determining transcription factor Prospero through a conserved binding motif and binds to genomic targets controlling EE cell fate and size, such as components of Notch and insulin/mTOR pathways. Collectively, our findings uncover a modality where changes in intracellular redox state serve as an instructive signal to control EE cell function to globally control organismal homeostasis.
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DOI: https://doi.org/10.1101/2025.06.30.662346
Lancet Oncol. 2025 Jul 02. pii: S1470-2045(25)00285-2. [Epub ahead of print]

Decoding the genomic landscape of early-onset colorectal cancer: the next chapter in precision oncology.

Andreas Seeber.

DOI: https://doi.org/10.1016/S1470-2045(25)00285-2
Cell Death Dis. 2025 Jul 10. 16(1): 510

PLIN2 promotes colorectal cancer progression through CD36-mediated epithelial-mesenchymal transition.

Fan Yang, Ying Li, Xue Shang, Yun Zhu, Wenting Hou, Yi Liu, Qing Hua, Zhirong Sun.

Colorectal cancer (CRC) is one of the most common malignant tumors with high incidence and mortality. The challenge remains to construct reliable prognostic prediction models and to further elucidate the key molecular mechanisms of tumor progression. To address this, we performed WGCNA based on 120 immune cell expression profiles from GEO sources to obtain a collection of monocytes/macrophages-related genes. The prognostic model was constructed by univariate survival analysis and LASSO regression analysis. Then, the prognostic model was validated by Multivariate Cox regression, Kaplan-Meier survival analysis and ROC analysis. In this prognostic model, we identified that PLIN2 has a potential value for CRC prognosis. PLIN2 expression in monocytes/macrophages was verified by scRNA-seq datasets and spatial transcriptome datasets, and PLIN2 was found to promote macrophage transformation to M2 subtype. Clinical specimens and tissue microarrays confirmed the differential expression and prognostic value of PLIN2 in CRC patients. Functional experiments demonstrated that PLIN2 gene overexpression promoted the proliferation, migration and invasion of CRC cells and significantly facilitated tumor growth in vivo. Mechanistically, we revealed that CD36 is a potential downstream target gene of PLIN2. The CD36 inhibitor Sulfo-N-succinimidyl Oleate significantly reversed PLIN2-induced proliferation, migration, invasion, and EMT activity of CRC cells in vitro and in vivo. Immunoprecipitation and immunofluorescence experiments confirmed that PLIN2 could interact with CD36. PLIN2 stabilized CD36 protein expression by inhibiting the proteasomal degradation pathway, thereby promoting CD36-mediated EMT activity. Overall, our study highlights that the PLIN2/CD36 axis regulates EMT activity and CRC progression, suggesting that interventions in this signaling pathway may offer a promising therapeutic approach to CRC progression. Schematic diagram elucidating the role of PLIN2 in CRC by Figdraw. FA is transported into the cell via CD36-mediated endocytosis. In CRC cells, PLIN2 promotes stability of CD36 and interacts with CD36 to activate the EMT process. However, the CD36 inhibitor SSO inhibits the binding of FAs to CD36 and attenuates its endocytosis, thereby reversing the PLIN2-mediated EMT process. Ultimately, the PLIN2-induced enhancement of CRC cell proliferation, migration, and invasion is attenuated by the CD36 inhibitor SSO.

DOI: https://doi.org/10.1038/s41419-025-07836-1
bioRxiv. 2025 Jul 02. pii: 2025.06.27.662039. [Epub ahead of print]

High Throughput Screening Identifies Small Molecules that Synergize with MRTX1133 Against Acquired Resistant KRAS G12D Mutated CRC.

Natalie Thielen, Ning Wei, Emiko Nagai, Edward Chu, Seiya Kitamura, Chaoyuan Kuang.

Colorectal cancer (CRC) remains a significant clinical challenge, with a 5-year survival rate of 10%. Over half of all CRCs harbor mutations in the KRAS gene, leading to poor response to standard therapy. This underscores the crucial need for novel therapeutics targeting KRAS and overcoming the growing barrier of resistance. To address these critical challenges, we conducted a high-throughput screen to identify small molecules that synergize with KRAS G12D inhibitor MRTX1133 against CRC. Through screening a 2,652 kinase inhibitor library, we discovered that Osimertinib and its analogs strongly synergize with MRTX1133 against both parental and MRTX1133-resistant cells. The top compound from the screen, NT-1, is a chemical analog of Osimertinib. NT-1 strongly synergized with MRTX1133 to suppress EGFR/MAPK signaling and induce apoptosis in an MRTX1133-resistant patient-derived organoid model of CRC. We present novel small molecule combinations with the potential to overcome the limitations of MRTX1133 with direct clinical translational applications.
One Sentence Summary: High throughput screening and validation in colon cancer PDOs identifies novel KRAS inhibitor combinations with potential for clinical translation.

DOI: https://doi.org/10.1101/2025.06.27.662039