bims-instec 2024-02-11 papers

bims-instec

Biomed News

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

Issue of 2024–02–11
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Clusterin: a marker and mediator of chemoresistance in colorectal cancer.
Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains.
Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation.
Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer.
MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer.
Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer.
SLE serum induces altered goblet cell differentiation and leakiness in human intestinal organoids.
Th17 cells secrete TWEAK to trigger epithelial-mesenchymal transition and promote colorectal cancer liver metastasis.
Pre-existing subclones determine radioresistance in rectal cancer organoids.
Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Cancer Metastasis Rev. 2024 Feb 06.

Clusterin: a marker and mediator of chemoresistance in colorectal cancer.

Sara Hlavca, Wing Hei Chan, Rebekah M Engel, Helen E Abud.

  Intra-tumoural heterogeneity and cancer cell plasticity in colorectal cancer (CRC) have been key challenges to effective treatment for patients. It has been suggested that a subpopulation of LGR5-expressing cancer stem cells (CSCs) is responsible for driving tumour relapse and therapy resistance in CRC. However, studies have revealed that the LGR5+ve CSC population is highly sensitive to chemotherapy. It has been hypothesised that another subset of tumour cells can phenotypically revert to a stem-like state in response to chemotherapy treatment which replenishes the LGR5+ve CSC population and maintains tumour growth. Recently, a unique stem cell population marked by enriched clusterin (CLU) expression and termed the revival stem cell (RevSC) was identified in the regenerating murine intestine. This CLU-expressing cell population is quiescent during homeostasis but has the ability to survive and regenerate other stem cells upon injury. More recently, the CLU+ve signature has been implicated in several adverse outcomes in CRC, including chemotherapy resistance and poor patient survival; however, the mechanism behind this remains undetermined. In this review, we discuss recent insights on CLU in CRC and its roles in enhancing the plasticity of cells and further consider the implications of CLU as a prospective target for therapeutic intervention.

Keywords:  CLU; Chemotherapy; Colorectal cancer; Regenerative stem cells; Tumour relapse

DOI:  https://doi.org/10.1007/s10555-024-10173-y
Nat Cell Biol. 2024 Feb 06.

Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains.

Rachel K Zwick, Petr Kasparek, Brisa Palikuqi, Sara Viragova, Laura Weichselbaum, Christopher S McGinnis, Kara L McKinley, Asoka Rathnayake, Dedeepya Vaka, Vinh Nguyen, Coralie Trentesaux, Efren Reyes, Alexander R Gupta, Zev J Gartner, Richard M Locksley, James M Gardner, Shalev Itzkovitz, Dario Boffelli, Ophir D Klein.

A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.

DOI: https://doi.org/10.1038/s41556-023-01337-z
Sci Adv. 2024 Feb 09. 10(6): eadi2671

Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation.

Jaakko Mattila, Arto Viitanen, Gaia Fabris, Tetiana Strutynska, Jerome Korzelius, Ville Hietakangas.

The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation. We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.

DOI: https://doi.org/10.1126/sciadv.adi2671
J Clin Invest. 2024 Feb 08. pii: e174545. [Epub ahead of print]

Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer.

Triet M Bui, Lenore K Yalom, Edward Ning, Jessica M Urbanczyk, Xingsheng Ren, Caroline J Herrnreiter, Jackson A DiSario, Brian Wray, Matthew J Schipma, Yuri S Velichko, David P Sullivan, Kouki Abe, Shannon M Lauberth, Guang-Yu Yang, Parambir S Dulai, Stephen B Hanauer, Ronen Sumagin.

  Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during inflammatory ulceration to CRC transition we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their localization to peripheral blood, inflamed colon, and tumors. In silico pathway overrepresentation analysis, protein-network mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA dataset and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in UC patients. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings, demonstrate a niche-directed PMN functional specialization, and identify TAN contributions to tumor vascularization, delineating a new therapeutic framework for CRC treatment focused on TAN angiogenic properties.

Keywords:  Cellular immune response; Colorectal cancer; Gastroenterology; Immunology; Neutrophils

DOI:  https://doi.org/10.1172/JCI174545
Cancers (Basel). 2024 Jan 31. pii: 604. [Epub ahead of print]16(3):

MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer.

Müge Erdem, Kyung Hwan Lee, Markus Hardt, Joseph L Regan, Dennis Kobelt, Wolfgang Walther, Margarita Mokrizkij, Christian Regenbrecht, Ulrike Stein.

  Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.

Keywords:  LGR5; MACC1; stemness; transcriptional regulation

DOI:  https://doi.org/10.3390/cancers16030604
J Transl Med. 2024 Feb 03. 22(1): 133

Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer.

Yuting Huang, Szehoi Chan, Shuna Chen, Xueqi Liu, Miao Li, Liyuan Zheng, Zhaoxia Dong, Ziyi Yang, Zixuan Liu, Disheng Zhou, Xingding Zhang, Bo Zhang.

   BACKGROUND: Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC.
METHODS: An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro.
RESULTS: Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP.
CONCLUSIONS: IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.

Keywords:  Apoptosis; Colorectal cancer; IMPDH2; Oxaliplatin resistance; Purine metabolism; β‑catenin

DOI:  https://doi.org/10.1186/s12967-024-04934-0
EMBO Mol Med. 2024 Feb 05.

SLE serum induces altered goblet cell differentiation and leakiness in human intestinal organoids.

Inga Viktoria Hensel, Szabolcs Éliás, Michelle Steinhauer, Bilgenaz Stoll, Salvatore Benfatto, Wolfgang Merkt, Stefan Krienke, Hanns-Martin Lorenz, Jürgen Haas, Brigitte Wildemann, Martin Resnik-Docampo.

  Human intestinal epithelial cells are the interface between luminal content and basally residing immune cells. They form a tight monolayer that constantly secretes mucus creating a multilayered protective barrier. Alterations in this barrier can lead to increased permeability which is common in systemic lupus erythematosus (SLE) patients. However, it remains unexplored how the barrier is affected. Here, we present an in vitro model specifically designed to examine the effects of SLE on epithelial cells. We utilize human colon organoids that are stimulated with serum from SLE patients. Combining transcriptomic with functional analyses revealed that SLE serum induced an expression profile marked by a reduction of goblet cell markers and changed mucus composition. In addition, organoids exhibited imbalanced cellular composition along with enhanced permeability, altered mitochondrial function, and an interferon gene signature. Similarly, transcriptomic analysis of SLE colon biopsies revealed a downregulation of secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.

Keywords:  Gut Leakiness; Intestinal Homeostasis; Organoids; Systemic Lupus Erythematosus (SLE); scRNA-seq

DOI:  https://doi.org/10.1038/s44321-024-00023-3
Cancer Res. 2024 Feb 09.

Th17 cells secrete TWEAK to trigger epithelial-mesenchymal transition and promote colorectal cancer liver metastasis.

Xin Liu, Xin Wang, Qingxia Yang, Li Luo, Ziqin Liu, Xiaoxue Ren, Kai Lei, Shangru Li, Zonglin Xie, Gaomin Zheng, Yifan Zhang, Yijie Hao, Qianying Zhou, Yingdong Hou, Fei Fang, Wu Song, Ji Cui, Jinping Ma, Wenxuan Xie, Shunli Shen, Ce Tang, Sui Peng, Jun Yu, Ming Kuang, Xinming Song, Fang Wang, Lixia Xu.

Liver metastasis is the leading cause of mortality in patients with colorectal cancer (CRC). Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in CRC liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multi-omics analysis of 130 samples from 18 synchronous CRLM patients integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of non-malignant cells between primary tumors from patients with metastatic CRC (mCRC) and non-metastatic CRC, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid-nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared to wild-type mice, while co-transfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in CRC patients. Additionally, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2123
Cell Rep. 2024 Feb 02. pii: S2211-1247(24)00063-9. [Epub ahead of print]43(2): 113735

Pre-existing subclones determine radioresistance in rectal cancer organoids.

Daan Andel, Bas Jeroen Viergever, Niek Alexander Peters, Danielle Adriana Elisabeth Raats, Susanne Jolien Schenning-van Schelven, Martijn Peter Willem Intven, Maurice Zandvliet, Jeroen Hagendoorn, Inne Hildbrand Max Borel Rinkes, Onno Kranenburg.

  More than half of all patients with cancer receive radiation therapy, but resistance is commonly observed. Currently, it is unknown whether resistance to radiation therapy is acquired or inherently present. Here, we employed organoids derived from rectal cancer and single-cell whole-genome sequencing to investigate the long-term evolution of subclones in response to radiation. Comparing single-cell whole-genome karyotypes between in-vitro-unirradiated and -irradiated organoids revealed three patterns of subclonal evolution: (1) subclonal persistence, (2) subclonal extinction, and (3) subclonal expansion. Organoids in which subclonal shifts occurred (i.e., expansion or extinction) became more resistant to radiation. Although radioresistant subclones did not share recurrent copy-number alterations that could explain their radioresistance, resistance was associated with reduced chromosomal instability, an association that was also observed in 529 human cancer cell lines. These data suggest that resistance to radiation is inherently present and associated with reduced chromosomal instability.

Keywords:  CP: Cancer; patient-derived organoids; radioresistance; rectal cancer; single-cell sequencing; tumor evolution

DOI:  https://doi.org/10.1016/j.celrep.2024.113735
Acta Pharm Sin B. 2024 Feb;14(2): 682-697

Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Shuran Fan, Ming Qi, Qi Qi, Qun Miao, Lijuan Deng, Jinghua Pan, Shenghui Qiu, Jiashuai He, Maohua Huang, Xiaobo Li, Jie Huang, Jiapeng Lin, Wenyu Lyu, Weiqing Deng, Yingyin He, Xuesong Liu, Lvfen Gao, Dongmei Zhang, Wencai Ye, Minfeng Chen.

  Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

Keywords:  Colorectal cancer; Epithelial–mesenchymal transition; Extracellular matrix remodeling; FAPα-activated prodrug; Fibroblast activation protein α; Immunosuppressive; Lymphatic metastasis; STAT3

DOI:  https://doi.org/10.1016/j.apsb.2023.11.002