bims-instec 2024-09-29 papers

bims-instec

Biomed News

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

Issue of 2024–09–29
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

ATF6 promotes colorectal cancer growth and stemness by regulating the Wnt pathway.
A Ctnnb1 enhancer transcriptionally regulates Wnt signaling dosage to balance homeostasis and tumorigenesis of intestinal epithelia.
Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers.
Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis.
Identifying targetable metabolic dependencies across colorectal cancer progression.
LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis.
GPR37 promotes colorectal cancer against ferroptosis by reprogramming lipid metabolism via p38-SCD1 axis.
Regulation of intestinal epithelial homeostasis by mesenchymal cells.
Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response.
Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer.
Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells.

Cancer Res Commun. 2025 Sep 26.

ATF6 promotes colorectal cancer growth and stemness by regulating the Wnt pathway.

Jeffrey J Rodvold, Matthew Grimmer, Karen Ruiz, Scot A Marsters, Ioanna Oikonomidi, Eileen Tan-Aristy, Victoria C Pham, Tamal Sarkar, Jonathan M Harnoss, Whitney Shatz-Binder, Zora D Modrusan, Thomas D Wu, Jennie R Lill, Elisia Villemure, Joachim Rudolph, Felipe de Sousa E Melo, Avi Ashkenazi.

The unfolded protein response maintains endoplasmic reticulum (ER) homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the ER-transmembrane proteins IRE1, PERK and ATF6. Malignant cells can co-opt IRE1 and PERK to sustain growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers including colorectal carcinoma (CRC). Genetic silencing or small molecule inhibition of ATF6 blocked cell cycle progression and reduced viability of several human CRC cell lines in vitro and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference disabled Wnt and Myc signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, decreasing Wnt-pathway activity and driving cellular differentiation. Wnt-surrogate agonism in a Wnt ligand-dependent CRC organoid restored pathway activity and rescued growth under ATF6 blockade. Our findings identify ATF6 as an unexpected facilitator of oncogenic Wnt signaling in CRC.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0268
Elife. 2024 Sep 25. pii: RP98238. [Epub ahead of print]13

A Ctnnb1 enhancer transcriptionally regulates Wnt signaling dosage to balance homeostasis and tumorigenesis of intestinal epithelia.

Xiaojiao Hua, Chen Zhao, Jianbo Tian, Junbao Wang, Xiaoping Miao, Gen Zheng, Min Wu, Mei Ye, Ying Liu, Yan Zhou.

  The β-catenin-dependent canonical Wnt signaling is pivotal in organ development, tissue homeostasis, and cancer. Here, we identified an upstream enhancer of Ctnnb1 - the coding gene for β-catenin, named ieCtnnb1 (intestinal enhancer of Ctnnb1), which is crucial for intestinal homeostasis. ieCtnnb1 is predominantly active in the base of small intestinal crypts and throughout the epithelia of large intestine. Knockout of ieCtnnb1 led to a reduction in Ctnnb1 transcription, compromising the canonical Wnt signaling in intestinal crypts. Single-cell sequencing revealed that ieCtnnb1 knockout altered epithelial compositions and potentially compromised functions of small intestinal crypts. While deletion of ieCtnnb1 hampered epithelial turnovers in physiologic conditions, it prevented occurrence and progression of Wnt/β-catenin-driven colorectal cancers. Human ieCTNNB1 drove reporter gene expression in a pattern highly similar to mouse ieCtnnb1. ieCTNNB1 contains a single-nucleotide polymorphism associated with CTNNB1 expression levels in human gastrointestinal epithelia. The enhancer activity of ieCTNNB1 in colorectal cancer tissues was stronger than that in adjacent normal tissues. HNF4α and phosphorylated CREB1 were identified as key trans-factors binding to ieCTNNB1 and regulating CTNNB1 transcription. Together, these findings unveil an enhancer-dependent mechanism controlling the dosage of Wnt signaling and homeostasis in intestinal epithelia.

Keywords:  Ctnnb1; canonical Wnt signaling; cell biology; colorectal cancer; enhancer; intestinal epithelial homeostasis; mouse

DOI:  https://doi.org/10.7554/eLife.98238
J Immunother Cancer. 2024 Sep 24. pii: e009602. [Epub ahead of print]12(9):

Metabolic reprogramming of hypoxic tumor-associated macrophages through CSF-1R targeting favors treatment efficiency in colorectal cancers.

Khaldoun Gharzeddine, Cristina Gonzalez Prieto, Marie Malier, Clara Hennot, Renata Grespan, Yoshiki Yamaryo-Botté, Cyrille Y Botté, Fabienne Thomas, Marie-Hélène Laverriere, Edouard Girard, Gael Roth, Arnaud Millet.

   BACKGROUND: Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colony-stimulating factor 1 receptor (CSF-1R) receptor is one of the most promising ones. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor.
METHODS: Using RNA sequencing and metabolomics approach, we characterize the reprogramming of human monocyte-derived macrophages under CSF-1R targeting.
RESULTS: We find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of sterol regulatory element-binding protein 2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of extracellular signal-regulated kinase 1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of hypoxic induced factor 2 alpha in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer.
CONCLUSIONS: These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages and its potential to reverse macrophage-mediated chemoresistance in colorectal tumors.

Keywords:  Chemotherapy; Cholesterol; Colorectal Cancer; Macrophage; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-009602
Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00339-2. [Epub ahead of print]77 103361

Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis.

Yunyi Bian, Guangyao Shan, Guoshu Bi, Jiaqi Liang, Zhengyang Hu, Qihai Sui, Haochun Shi, Zhaolin Zheng, Guangyu Yao, Qun Wang, Hong Fan, Cheng Zhan.

  KRAS is among the most commonly mutated oncogenes in human malignancies. Although the advent of sotorasib and adagrasib, has lifted the "undruggable" stigma of KRAS, the resistance to KRAS inhibitors quickly becomes a major issue. Here, we reported that aldehyde dehydrogenase 1 family member A1 (ALDH1A1), an enzyme in retinoic acid biosynthesis and redox balance, increases in response to KRAS inhibitors and confers resistance in a range of cancer types. KRAS inhibitors' efficacy is significantly improved in sensitive or drug-resistant cells, patient-derived organoids (PDO), and xenograft models by ALDH1A1 knockout, loss of enzyme function, or inhibitor. Furthermore, we discovered that ALDH1A1 suppresses the efficacy of KRAS inhibitors by counteracting ferroptosis. ALDH1A1 detoxicates deleterious aldehydes, boosts the synthesis of NADH and retinoic acid (RA), and improves RARA function. ALDH1A1 also activates the CREB1/GPX4 pathway, stimulates the production of lipid droplets in a pH-dependent manner, and subsequently prevents ferroptosis induced by KRAS inhibitors. Meanwhile, we established that GTF2I is dephosphorylated at S784 via ERK by KRAS inhibitors, which hinders its nuclear translocation and mediates ALDH1A1's upregulation in response to KRAS inhibitors. In summary, the results offer valuable insights into targeting ALDH1A1 to enhance the effectiveness of KRAS-targeted therapy through ferroptosis in cancer treatment.

Keywords:  ALDH1A1; Ferroptosis; GTF2I; KRAS-targeted drug resistance

DOI:  https://doi.org/10.1016/j.redox.2024.103361
Mol Metab. 2024 Sep 25. pii: S2212-8778(24)00168-6. [Epub ahead of print] 102037

Identifying targetable metabolic dependencies across colorectal cancer progression.

Danny N Legge, Tracey J Collard, Ewelina Stanko, Ashley J Hoskin, Amy K Holt, Caroline J Bull, Madhu Kollareddy, Jake Bellamy, Sarah Groves, Eric H Ma, Emma Hazelwood, David Qualtrough, Borko Amulic, Karim Malik, Ann C Williams, Nicholas Jones, Emma E Vincent.

  Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system - comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

Keywords:  Colorectal cancer; adenocarcinoma; adenoma; asparagine; asparagine synthetase; oncometabolism

DOI:  https://doi.org/10.1016/j.molmet.2024.102037
Redox Biol. 2024 Sep 18. pii: S2213-2317(24)00340-9. [Epub ahead of print]77 103362

LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis.

Zechang Xin, Chenyu Hu, Chunfeng Zhang, Ming Liu, Juan Li, Xiaoyan Sun, Yang Hu, Xiaofeng Liu, Kun Wang.

  Upon chemotherapy, excessive reactive oxygen species (ROS) often lead to the production of massive lipid peroxides in cancer cells and induce cell death, namely ferroptosis. The elimination of ROS is pivotal for tumor cells to escape from ferroptosis and acquire drug resistance. Nevertheless, the precise functions of long non-coding RNAs (lncRNAs) in ROS metabolism and tumor drug-resistance remain elusive. In this study, we identify LncRNA-HMG as a chemoresistance-related lncRNA in colorectal cancer (CRC) by high-throughput screening. Abnormally high expression of LncRNA-HMG predicts poorer prognosis in CRC patients. Concurrently, we found that LncRNA-HMG protects CRC cells from ferroptosis upon chemotherapy, thus enhancing drug resistance of CRC cells. LncRNA-HMG binds to p53 and facilitates MDM2-mediated degradation of p53. Decreased p53 induces upregulation of SLC7A11 and VKORC1L1, which contribute to increase the supply of reducing agents and eliminate excessive ROS. Consequently, CRC cells escape from ferroptosis and acquire chemoresistance. Importantly, inhibition of LncRNA-HMG by anti-sense oligo (ASO) dramatically sensitizes CRC cells to chemotherapy in patient-derived xenograft (PDX) model. LncRNA-HMG is also a transcriptional target of β-catenin/TCF and activated Wnt signals trigger the marked upregulation of LncRNA-HMG. Collectively, these findings demonstrate that LncRNA-HMG promotes CRC chemoresistance and might be a prognostic or therapeutic target for CRC.

Keywords:  Chemoresistance; Colorectal cancer; Ferroptosis; LncRNA-HMG; p53

DOI:  https://doi.org/10.1016/j.redox.2024.103362
Apoptosis. 2024 Sep 21.

GPR37 promotes colorectal cancer against ferroptosis by reprogramming lipid metabolism via p38-SCD1 axis.

Jiamin Zhou, Xigan He, Weixing Dai, Qingguo Li, Zhen Xiang, Yixiu Wang, Ti Zhang, Weiqi Xu, Lu Wang, Anrong Mao.

  Colorectal cancer (CRC) is a prevalent malignant tumor worldwide, leading to significant morbidity and disease burden. Diagnostic indicators and treatment objectives for CRC are urgently needed. This study demonstrates that GPR37, a GPCR receptor, is highly expressed in CRC. Depletion of GPR37 significantly reduced CRC tumor cell growth both in vitro and in vivo. Further tests showed that GPR37 protects cancer cells from ferroptosis by upregulating SCD1 expression, thereby modulating lipid metabolism, suppressing the level of reactive oxygen species, and mitigating ferroptosis. Mechanistic studies have shown that GPR37 modulates lipid metabolism in tumor cells by promoting SCD1 transcription via the MAPK-p38 signaling pathway. Our results reveal the pro-carcinogenic effect of GPR37 in primary CRC and suggest that targeting GPR37 could be a potential therapeutic target for CRC.

Keywords:  Ferroptosis; GPR37; Lipid metabolism; SCD1; p38

DOI:  https://doi.org/10.1007/s10495-024-02018-4
Inflamm Regen. 2024 Sep 26. 44(1): 42

Regulation of intestinal epithelial homeostasis by mesenchymal cells.

Hisako Kayama, Kiyoshi Takeda.

  The gastrointestinal tract harbors diverse microorganisms in the lumen. Epithelial cells segregate the luminal microorganisms from immune cells in the lamina propria by constructing chemical and physical barriers through the production of various factors to prevent excessive immune responses against microbes. Therefore, perturbations of epithelial integrity are linked to the development of gastrointestinal disorders. Several mesenchymal stromal cell populations, including fibroblasts, myofibroblasts, pericytes, and myocytes, contribute to the establishment and maintenance of epithelial homeostasis in the gut through regulation of the self-renewal, proliferation, and differentiation of intestinal stem cells. Recent studies have revealed alterations in the composition of intestinal mesenchymal stromal cells in patients with inflammatory bowel disease and colorectal cancer. A better understanding of the interplay between mesenchymal stromal cells and epithelial cells associated with intestinal health and diseases will facilitate identification of novel biomarkers and therapeutic targets for gastrointestinal disorders. This review summarizes the key findings obtained to date on the mechanisms by which functionally distinct mesenchymal stromal cells regulate epithelial integrity in intestinal health and diseases at different developmental stages.

Keywords:  Colorectal cancer; Crohn’s disease; Epithelial cell; Inflammatory bowel disease; Intestinal stem cell; Mesenchymal stromal cell; Ulcerative colitis

DOI:  https://doi.org/10.1186/s41232-024-00355-0
Nat Rev Clin Oncol. 2024 Sep 24.

Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response.

Christopher J M Williams, Allyson M Peddle, Pashtoon M Kasi, Jenny F Seligmann, Campbell S Roxburgh, Gary M Middleton, Sabine Tejpar.

Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant 'window-of-opportunity' trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance.

DOI: https://doi.org/10.1038/s41571-024-00943-6
Sci Adv. 2024 Sep 27. 10(39): eado1458

Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer.

Rachel C Fellows, Sung Kook Chun, Natalie Larson, Bridget M Fortin, Alisa L Mahieu, Wei A Song, Marcus M Seldin, Nicholas R Pannunzio, Selma Masri.

Diet is a robust entrainment cue that regulates diurnal rhythms of the gut microbiome. We and others have shown that disruption of the circadian clock drives the progression of colorectal cancer (CRC). While certain bacterial species have been suggested to play driver roles in CRC, it is unknown whether the intestinal clock impinges on the microbiome to accelerate CRC pathogenesis. To address this, genetic disruption of the circadian clock, in an Apc-driven mouse model of CRC, was used to define the impact on the gut microbiome. When clock disruption is combined with CRC, metagenomic sequencing identified dysregulation of many bacterial genera including Bacteroides, Helicobacter, and Megasphaera. We identify functional changes to microbial pathways including dysregulated nucleic acid, amino acid, and carbohydrate metabolism, as well as disruption of intestinal barrier function. Our findings suggest that clock disruption impinges on microbiota composition and intestinal permeability that may contribute to CRC pathogenesis.

DOI: https://doi.org/10.1126/sciadv.ado1458
Cancer Sci. 2024 Sep 22.

Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells.

Kumiko Taniguchi, Kei Sugihara, Takashi Miura, Daisuke Hoshi, Susumu Kohno, Chiaki Takahashi, Eishu Hirata, Etsuko Kiyokawa.

  Metastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active KRAS mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. In vitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates in vitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl-CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death in vitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol-dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients.

Keywords:  cholesterol; colorectal cancer; extravasation; fatty acid; liver metastasis

DOI:  https://doi.org/10.1111/cas.16331