bims-instec 2024-12-29 papers

bims-instec

Biomed News

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

Issue of 2024–12–29
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Paneth Cells: Dispensable yet Irreplaceable for the Intestinal Stem Cell Niche.
Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer.
WNT4 promotes the symmetric fission of crypt in radiation-induced intestinal epithelial regeneration.
NanoCMSer: a consensus molecular subtype stratification tool for fresh-frozen and paraffin-embedded colorectal cancer samples.
Wnt/β-catenin pathway as a link between therapy resistance-driven epithelial-mesenchymal transition and stemness in colorectal cancer.
Intestinal organoid co-culture systems: current approaches, challenges, and future directions.
Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
Mevalonate kinase inhibits anti-tumor immunity by impairing the tumor cell-intrinsic interferon response in microsatellite instability colorectal cancer.
FGF19-Activated Hepatic Stellate Cells Release ANGPTL4 that Promotes Colorectal Cancer Liver Metastasis.

Cell Mol Gastroenterol Hepatol. 2024 Dec 19. pii: S2352-345X(24)00198-X. [Epub ahead of print] 101443

Paneth Cells: Dispensable yet Irreplaceable for the Intestinal Stem Cell Niche.

Michaela Quintero, Linda C Samuelson.

  Intestinal stem cells replenish the epithelium throughout life by continuously generating intestinal epithelial cell types, including absorptive enterocytes, and secretory goblet, endocrine, and Paneth cells. This process is orchestrated by a symphony of niche factors required to maintain intestinal stem cells and to direct their proliferation and differentiation. Among the various mature intestinal epithelial cell types, Paneth cells are unique in their location in the stem cell zone, directly adjacent to intestinal stem cells. Although Paneth cells were first described as an epithelial cell component of the innate immune system due to their expression of anti-microbial peptides, they have been proposed to be niche cells due to their close proximity to intestinal stem cells and expression of niche factors. However, function as a niche cell has been debated since mice lacking Paneth cells retain functional stem cells that continue to replenish the intestinal epithelium. In this review, we summarize the intestinal stem cell niche, including the Notch, Wnt, growth factor, mechanical, and metabolic niche, and discuss how Paneth cells might contribute to these various components. We also present a nuanced view of the Paneth cell as a niche cell. Although not required, Paneth cells enhance stem cell function, particularly during intestinal development and regeneration. Furthermore, we suggest that Paneth cell loss induces ISC remodeling to adjust their niche demands.

Keywords:  Intestinal crypt; Notch signaling; WNT signaling; cellular remodeling; tissue regeneration

DOI:  https://doi.org/10.1016/j.jcmgh.2024.101443
Redox Biol. 2024 Dec 11. pii: S2213-2317(24)00436-1. [Epub ahead of print]79 103458

Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer.

Eeshrita Jog, Ashwin Kumar Jainarayanan, Alessandro La Ferlita, Arnab Chakraborty, Afiya Dalwai, Showket Yahya, Anusha Shivashankar, Bhagya Shree Choudhary, Aakash Chandramouli, Mufaddal Kazi, Darshan Jain, Nileema Khapare, Akshaya B, Bushra K Khan, Poonam Gera, Prachi Patil, Rahul Thorat, Nandini Verma, Lalit Sehgal, Avanish Saklani, Siddhesh S Kamat, Sorab N Dalal, Nazia Chaudhary.

  A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) in vitro. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.

Keywords:  De novo lipogenesis; Drug tolerant persister cells; Ferroptosis; Lipid droplet; Lipin1; Non-responder

DOI:  https://doi.org/10.1016/j.redox.2024.103458
Cell Mol Biol Lett. 2024 Dec 26. 29(1): 158

WNT4 promotes the symmetric fission of crypt in radiation-induced intestinal epithelial regeneration.

Jingyang Cheng, Haiyong Wu, Yanmei Cui.

   BACKGROUND: Radiotherapy for pelvic malignant tumors inevitably causes intestinal tissue damage. The regeneration of intestinal epithelium after radiation injury relies mainly on crypt fission. However, little is known about the regulatory mechanisms of crypt fission events.
METHODS: The effects of WNT4 on crypt regeneration and the symmetry of crypt fission were examined using a mouse small intestinal organoid culture model. Three-dimensional (3D) reconstructed images of organoids were applied to assess the symmetry of crypt fission and Paneth cell localization upon manipulation of WNT4 expression. The effect of WNT4 on the expression of β-catenin target genes was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). The in vivo effect of WNT4 overexpression mediated by adeno-associated virus (AAV) on symmetric fission of crypt was investigated using a radiation-injured mouse model.
RESULTS: WNT4 has a special function of promoting symmetric fission of small intestinal crypts, although it inhibits budding, stemness, and cell proliferation on organoids. WNT4 promotes the correct localization of Paneth cells in the crypt base by regulating the expression of EphB3, thereby promoting the symmetric fission of small intestinal crypts. WNT4 negatively regulates the canonical WNT/β-catenin signaling pathway, and it promotes symmetric crypt fission in a ROR2 receptor-dependent manner. Moreover, in patients and animal models of radiation-induced intestinal injury, we found that the regenerated crypts are irregular in size and shape, Paneth cells are mislocalized, and the expression of WNT4 is decreased while EphB3 is increased. Importantly, restoration of WNT4 expression mediated by AAV effectively promotes symmetric crypt fission and thus improves the regularity of regenerating crypts in mice with radiation-induced injury.
CONCLUSIONS: Our study highlights the critical role of WNT4 in the regulation of crypt fission and provides WNT4 as a potential therapeutic target for radiation enteritis.

Keywords:  Crypt fission; Epithelial regeneration; Paneth cell; WNT4

DOI:  https://doi.org/10.1186/s11658-024-00677-4
Mol Oncol. 2024 Dec 25.

NanoCMSer: a consensus molecular subtype stratification tool for fresh-frozen and paraffin-embedded colorectal cancer samples.

Arezo Torang, Simone van de Weerd, Veerle Lammers, Sander van Hooff, Inge van den Berg, Saskia van den Bergh, Miriam Koopman, Jan N IJzermans, Jeanine M L Roodhart, Jan Koster, Jan Paul Medema.

  Colorectal cancer (CRC) is a significant contributor to cancer-related mortality, emphasizing the need for advanced biomarkers to guide treatment. As part of an international consortium, we previously categorized CRCs into four consensus molecular subtypes (CMS1-CMS4), showing promise for outcome prediction. To facilitate clinical integration of CMS classification in settings where formalin-fixed paraffin-embedded (FFPE) samples are routinely used, we developed NanoCMSer, a NanoString-based CMS classifier using 55 genes. NanoCMSer achieved high accuracy rates, with 95% for fresh-frozen samples from the MATCH cohort and 92% for FFPE samples from the CODE cohort, marking the highest reported accuracy for FFPE tissues to date. Additionally, it demonstrated 96% accuracy across a comprehensive collection of 23 RNAseq-based datasets, compiled in this study, surpassing the performance of existing models. Classifying with only 55 genes, the CMS predictions were still biologically relevant, recognizing CMS-specific biology upon enrichment analysis. Additionally, we observed substantial differences in recurrence-free survival curves when comparing CMS2/3 patients in stage III versus II. Probability of recurrence after 5 years increased by 21% in CMS2 and 31% in CMS3 for patients in stage III, whereas this difference was less pronounced for CMS1 and CMS4, with 11% and 10%, respectively. We posit NanoCMSer as a robust tool for subtyping CRCs for both tumor biology and clinical practice, accessible via nanocmser r package (https://github.com/LEXORlab/NanoCMSer) and Shinyapp (https://atorang.shinyapps.io/NanoCMSer).

Keywords:  NanoString; colorectal cancer; consensus molecular subtypes; machine learning; prognosis biomarker

DOI:  https://doi.org/10.1002/1878-0261.13781
Cell Biol Int. 2024 Dec 20.

Wnt/β-catenin pathway as a link between therapy resistance-driven epithelial-mesenchymal transition and stemness in colorectal cancer.

Murilo Ramos Rocha, Yuri Kelly Castillo-Medina, Bárbara Martins de Lima Coelho, Luidy Lucas Lopes Rios, Jose Andres Morgado-Diaz.

  The high plasticity of cells undergoing epithelial-mesenchymal transition (EMT) promotes increased tumor heterogeneity, and its interaction with tumor-associated stromal cells appears to contribute to developing a stemness phenotype. Cells with these characteristics exhibit increased resistance to chemotherapy and radiotherapy, leading to disease relapse and metastasis. Here, we discuss the activation of the Wnt/β-catenin pathway in promoting EMT and stemness within the context of cellular resistance to these therapies. We discuss whether EMT and cancer stem cells (CSCs) function in conjunction, independently, or if a link is connecting their development. We further propose that this pathway is necessary to establish a connection between these two phenotypes. And suggest that it could hinder the rise of CSCs from treatment-induced EMT cells when inhibited. Understanding this cellular phenomenon might allow the development of new targeted therapies to improve clinical responses, particularly in colorectal cancer.

Keywords:  Wnt/β‐catenin pathway; epithelial‐mesenchymal transition; stemness; therapy resistance

DOI:  https://doi.org/10.1002/cbin.12270
Am J Physiol Gastrointest Liver Physiol. 2024 Dec 23.

Intestinal organoid co-culture systems: current approaches, challenges, and future directions.

Ghanyah Al-Qadami, Anita Raposo, Chia-Chi Chien, Chenkai Ma, Ilka Priebe, Maryam Hor, Kim Fung.

  The intestinal microenvironment represents a complex and dynamic ecosystem, comprising a diverse range of epithelial and non-epithelial cells, a protective mucus layer, and a diverse community of gut microbiota. Understanding the intricate interplay between these components is essential for uncovering the mechanisms underlying intestinal health and disease. The development of intestinal organoids, 3D mini-intestines that closely mimic the architecture, cellular diversity, and functionality of the intestine, offers a powerful platform for investigating different aspects of intestinal physiology and pathology. However, current intestinal organoid models, mainly adult stem cell-derived organoids, lack the non-epithelial and microbial components of the intestinal microenvironment. As such, several co-culture systems have been developed to co-culture intestinal organoids with other intestinal elements including microbes (bacteria and viruses) and immune, stromal, and neural cells. These co-culture models allow researchers to recreate the complex intestinal environment and study the intricate crosstalk between different components of the intestinal ecosystem under healthy and pathological conditions. Currently, there are several approaches and methodologies to establish intestinal organoid co-cultures, and each approach has its own strengths and limitations. This review discusses the existing methods for co-culturing intestinal organoids with different intestinal elements, focusing on the methodological approaches, strengths and limitations, and future directions.

Keywords:  Co-culture; Immune cells; Intestinal organoids; Microbes; Stromal cells

DOI:  https://doi.org/10.1152/ajpgi.00203.2024
bioRxiv. 2024 Dec 10. pii: 2024.12.06.626451. [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.

Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.
BRIEF SUMMARY: HDAC1/2 inhibition promotes colorectal cancer differentiation via gains in H3K27ac, which can be reversed by blocking its acetyltransferase EP300.

DOI: https://doi.org/10.1101/2024.12.06.626451
Oncogene. 2024 Dec 26.

Mevalonate kinase inhibits anti-tumor immunity by impairing the tumor cell-intrinsic interferon response in microsatellite instability colorectal cancer.

Yuanyu Liao, Rui Yang, Bojun Wang, Yuli Ruan, Luying Cui, Jiani Yang, Xuefan Yu, Shuling Han, Yuanfei Yao, Xindi Luan, Yingjue Li, Mengde Shi, Shuijie Li, Chao Liu, Yanqiao Zhang.

Insufficient tumor cell-intrinsic interferon response represents a major obstacle in immune checkpoint blockade (ICB) therapy, particularly in anti-PD-1 treatment. Although cholesterol metabolism has been demonstrated to be a critical regulator of anti-tumor immune responses, whether cholesterol influences tumor cell-intrinsic interferon response in microsatellite instability (MSI) colorectal cancer (CRC) remains unknown. Through comprehensive siRNA library screening and Gene Set Enrichment Analysis (GSEA), we identified mevalonate kinase (MVK) as a crucial negative regulator of tumor cell-intrinsic interferon response in MSI CRC cells. Genetic ablation of MVK resulted in significant upregulation of Th1 type chemokines (CXCL9 and CXCL10) and enhanced CD8+T cell infiltration in MSI CRC, consequently leading to marked tumor growth suppression in immunocompetent mice. At the molecular level, we demonstrated that MVK physically interacts with the transcriptional activation domain (TAD) of signal transducer and activator of transcription 1 (STAT1). This interaction substantially impairs STAT1 nuclear translocation, thereby attenuating interferon signaling cascade. Furthermore, analyses of humanized PBMC-PDX models and clinical cohorts of MSI CRC patients revealed that reduced MVK expression in tumor tissues strongly correlates with favorable responses to anti-PD-1 therapy. Collectively, our findings establish MVK as a pivotal mediator in cholesterol synthesis pathway that negatively regulates tumor cell-intrinsic interferon response in MSI CRC. These results suggest that therapeutic targeting of MVK represents a promising strategy to enhance ICB efficacy through potentiation of interferon responses in MSI CRC patients.

DOI: https://doi.org/10.1038/s41388-024-03255-2
Adv Sci (Weinh). 2024 Dec 24. e2413525

FGF19-Activated Hepatic Stellate Cells Release ANGPTL4 that Promotes Colorectal Cancer Liver Metastasis.

Xueying Fan, Baoting Li, Fan Zhang, Meng Liu, Hiu-Yee Kwan, Zhongqiu Liu, Tao Su.

  Liver and lung are the most common metastatic sites in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a crucial role in the progression and metastasis of CRC. Understanding the interactions between various types of cells in the TME can suggest innovative therapeutic strategies. Using single-cell RNA sequencing (scRNA-Seq) and clinical samples, fibroblast growth factor-19 (FGF19, rodent FGF15) is found to mediate a significant interaction between CRC cells and cancer-associated fibroblasts (CAFs), activating the hepatic stellate cells (HSCs)-to-CAFs differentiation. In various CRC metastatic mouse models, it is shown that FGF15 has a more pronounced effect on liver metastasis compared to pulmonary metastasis. More importantly, the differentially expressed genes (DEGs) are also identified from the RNA-Seq dataset upon the activation of HSCs by FGF19 and compared the DEGs in matched primary and metastatic mRNA samples from patients with CRC liver metastasis (CRCLM), it is found that the ANGPTL4 gene is significantly associated with HSCs activation. Different mouse models also demonstrated the impact of the FGF19/ANGPTL4 axis on the severity of CRCLM. Importantly, disruption of this axis significantly inhibits CRCLM in vivo. This study is among the first to demonstrate the impact of the FGF19/ANGPTL4 axis on CRCLM, offering a novel therapeutic strategy.

Keywords:  ANGPTL4; FGF19; cancer‐associated fibroblasts; colorectal cancer liver metastasis; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202413525