bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–11–24
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources.
  2. Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome.
  3. Liver X receptor unlinks intestinal regeneration and tumorigenesis.
  4. Single-cell RNA-seq analysis of cancer-endothelial cell interactions in primary tumor and peritoneal metastasis from a single patient with colorectal cancer.
  5. Non-canonical metastatic colorectal cancer.
  6. LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF V600E colorectal cancer.
  7. Mapping and tracing Grem1+ stromal cells in an Apc Min/+ mouse utilizing cryopreserved intestinal sections prepared via modified Swiss-roll technique.
  8. CBLN2 overexpression inhibits colorectal cancer progression and improves immunotherapy responses.
  9. Characterizing PANoptosis gene signature in prognosis and chemosensitivity of colorectal cancer.
  10. DUSP6 regulates Notch1 signalling in colorectal cancer.
  11. Dietary Lipids and Their Metabolism in the Midgut.
  12. Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer.
  13. The role of negative hyperselection in metastatic colorectal cancer.
  14. Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo.
  1. Nat Commun. 2024 Nov 21. 15(1): 10107
    Acid-exposed and hypoxic cancer cells do not overlap but are interdependent for unsaturated fatty acid resources.
    Katarzyna Głowacka, Sébastien Ibanez, Ophélie Renoult, Perrine Vermonden, Maria Virginia Giolito, Kübra Özkan, Charline Degavre, Léo Aubert, Céline Guilbaud, Florine Laloux-Morris, Elena Richiardone, Jérôme Ambroise, Caroline Bouzin, Davide Brusa, Jonas Dehairs, Johan Swinnen, Cyril Corbet, Yvan Larondelle, Olivier Feron.
      Cancer cells in acidic tumor regions are aggressive and a key therapeutic target, but distinguishing between acid-exposed and hypoxic cells is challenging. Here, we use carbonic anhydrase 9 (CA9) antibodies to mark acidic areas in both hypoxic and respiring tumor areas, along with an HRE-GFP reporter for hypoxia, to isolate distinct cell populations from 3D tumor spheroids. Transcriptomic analysis of CA9-positive, hypoxia-negative cells highlights enriched fatty acid desaturase activity. Inhibiting or silencing stearoyl-CoA desaturase-1 (SCD1) induces ferroptosis in CA9-positive acidic cancer cells and delays mouse tumor growth, an effect enhanced by omega-3 fatty acid supplementation. Using acid-exposed cancer cells and patient-derived tumor organoids, we show that SCD1 inhibition increases acidic cancer cell reliance on external mono-unsaturated fatty acids, depriving hypoxic cells of essential resources. This bystander effect provides unbiased evidence for a lack of full overlap between hypoxic and acidic tumor compartments, highlighting a rationale for targeting desaturase activity in cancer.
    DOI:  https://doi.org/10.1038/s41467-024-54435-3
  2. Gut. 2024 Nov 19. pii: gutjnl-2024-332752. [Epub ahead of print]
    Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome.
    Laura J Schwarzmueller, Ronja S Adam, Leandro F Moreno, Lisanne E Nijman, Adrian Logiantara, Steven Eleonora, Oscar Bril, Sophie Vromans, Nina E de Groot, Francesca Paola Giugliano, Ekaterina Stepanova, Vanesa Muncan, Clara C Elbers, Kristiaan J Lenos, Danny A Zwijnenburg, Monique A J van Eijndhoven, Dirk Michiel Pegtel, Sanne M van Neerven, Fabricio Loayza-Puch, Tulin Dadali, Wendy J Broom, Martin A Maier, Jan Koster, Louis Vermeulen, Nicolas Léveillé.
       BACKGROUND: Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved.
    OBJECTIVE: In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets.
    DESIGN: We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC.
    RESULTS: We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo.
    CONCLUSION: We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition.
    Keywords:  colorectal cancer
    DOI:  https://doi.org/10.1136/gutjnl-2024-332752
  3. Nature. 2024 Nov 20.
    Liver X receptor unlinks intestinal regeneration and tumorigenesis.
    Srustidhar Das, S Martina Parigi, Xinxin Luo, Jennifer Fransson, Bianca C Kern, Ali Okhovat, Oscar E Diaz, Chiara Sorini, Paulo Czarnewski, Anna T Webb, Rodrigo A Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J Villablanca.
      Uncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-08247-6
  4. BJC Rep. 2024 Nov 18. 2(1): 88
    Single-cell RNA-seq analysis of cancer-endothelial cell interactions in primary tumor and peritoneal metastasis from a single patient with colorectal cancer.
    Yuri Sakimoto, Kohei Kumegawa, Shimpei Matsui, Tomohiro Yamaguchi, Toshiki Mukai, Koji Okabayashi, Seiichi Mori, Yuko Kitagawa, Takashi Akiyoshi, Reo Maruyama.
       BACKGROUND: Peritoneal metastasis, a major complication of colorectal cancer (CRC), often leads to poor quality of life and unfavorable outcomes. Despite numerous studies characterizing its biological features in CRC, intratumor heterogeneity and interactions between cancer cells and tumor microenvironment cells remain poorly understood.
    METHODS: To explore these aspects, we performed single-cell transcriptome analysis of matched primary tumor and peritoneal metastasis samples from a treatment-naïve patient.
    RESULTS: Our analysis revealed enrichment of "tip" endothelial cells in the primary tumor, driving angiogenic sprouting, whereas these cells were absent in peritoneal metastases. Moreover, cancer cells in peritoneal metastasis displayed a distinct expression signature associated with epithelial-mesenchymal transition and tumor invasiveness. Analysis of cell-cell communication between endothelial and tumor cells revealed decreased VEGF signaling and increased CXCL-ACKR1 interactions in peritoneal metastasis.
    CONCLUSIONS: Although limited by its N-of-1 design and requiring further validation, our study provides preliminary observations suggesting that alterations in cancer-endothelial cell interactions could reduce dependence on VEGF signaling and influence immune cell infiltration in CRC peritoneal metastasis.
    DOI:  https://doi.org/10.1038/s44276-024-00112-3
  5. Nat Rev Gastroenterol Hepatol. 2024 Nov 21.
    Non-canonical metastatic colorectal cancer.
    Eleni Kotsiliti.
      
    DOI:  https://doi.org/10.1038/s41575-024-01026-8
  6. bioRxiv. 2024 Oct 29. pii: 2024.10.25.620306. [Epub ahead of print]
    LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF V600E colorectal cancer.
    Christopher A Ladaika, Averi Chakraborty, Ashiq Masood, Galen Hostetter, Joo Mi Yi, Heather M O'Hagan.
      BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAF V600E CRC is treatment with BRAF and EGFR inhibitors. However, responses are not durable. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAF V600E CRC as compared to BRAF wildtype CRC. Here, we demonstrated that combined BRAF and EGFR inhibition enriches for EECs in several models of BRAF V600E CRC. Additionally, EECs and other secretory cell types were enriched in a subset of BRAF V600E CRC patient samples following targeted therapy. Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3.
    Statement of Significance: Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.
    DOI:  https://doi.org/10.1101/2024.10.25.620306
  7. iScience. 2024 Nov 15. 27(11): 111173
    Mapping and tracing Grem1+ stromal cells in an Apc Min/+ mouse utilizing cryopreserved intestinal sections prepared via modified Swiss-roll technique.
    Youheng Jiang, Zhang Fu, Yanfang Chen, Qunlong Jin, Yanming Yang, Zerong Lin, Changxue Li, Yunfei Gao, Zepeng Dong, Yang He, Xinjun Mao, Yulong He, Qingyuan Zhang, Qi Zhang, Ningning Li.
      Grem1+ cancer-associated fibroblasts (CAFs) are crucial in colorectal cancer (CRC) development, yet technical challenges have limited understanding of their origins, spatiotemporal distribution, and potential roles. Here, we devised a custom mold, optimizing the gut Swiss-roll technique to create a single cryopreserved slide for comprehensive staining. Our integrated approach uncovered a marked increase in Grem1+ CAFs within Apc Min/+ mouse tumors at 12 weeks, compared to normal mucosa. Subsequent lineage tracing in Grem1-CreER T2 ; R26-LSL-tdTomato; Apc Min/+ mice revealed that most Grem1+ CAFs infiltrating the tumor core originated from Grem1+ intestinal reticular stem cells (iRSCs). A minor subset of Grem1+ CAFs, located in the submucosa, retained characteristics of Grem1+ intestinal sub-epithelial myofibroblasts (ISEMFs). Altogether, CAFs derived from Grem1+ iRSCs may serve as a principal stromal cell type driving early-stage CRC progression, while Grem1+ ISEMFs contribute less from a more distant location. Hence, targeting Grem1+ CAFs presents an early and promising therapeutic strategy in CRC.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111173
  8. Int Immunopharmacol. 2024 Nov 21. pii: S1567-5769(24)02088-5. [Epub ahead of print]144 113566
    CBLN2 overexpression inhibits colorectal cancer progression and improves immunotherapy responses.
    Zeyu Wang, Hongjing Pan, Jun Zhou, Dong Wan.
      Cerebellin 2 (CBLN2) has critical roles in regulating neuronal function, however, its functions in cancer are poorly studied. In our project, we found that CBLN2 expression is significantly downregulated in colorectal carcinoma (CRC), which is related to poor outcomes of CRC patients. In addition, we found that CBLN2 is closely associated with immune infiltrates in CRC samples, especially CD8 + T cells. Mechanistically, we discovered that CBLN2 could inhibit STAT3-induced PD-L1 and beta-catenin activation in CRC. Further experiments revealed that CBLN2 overexpression could inhibit oncogenic properties of CRC cells in vitro and CRC tumor growth in vivo. What's more, we also confirmed that the activation of CBLN2 could improve the efficiency of immune checkpoint blockade (ICB) treatment in the MC38 CRC model. In conclusion, the CBLN2-STAT3 axis may act as a novel potential target for CRC treatment.
    Keywords:  CBLN2; Colorectal carcinoma; Immunotherapy; PD-L1; STAT3 signaling pathway
    DOI:  https://doi.org/10.1016/j.intimp.2024.113566
  9. J Gastrointest Oncol. 2024 Oct 31. 15(5): 2129-2144
    Characterizing PANoptosis gene signature in prognosis and chemosensitivity of colorectal cancer.
    Tingyu Zhao, Xiao Zhang, Xiao Liu, Xingyu Jiang, Silu Chen, Huiqin Li, Hongsheng Ji, Sumeng Wang, Qi Liang, Siqi Ni, Mulong Du, Lingxiang Liu.
       Background: PANoptosis is a cell death pathway involved in pyroptosis, apoptosis and necrosis, and plays a key role in the development of malignant tumors. However, the molecular signature of PANoptosis in colorectal cancer (CRC) prognosis has not been thoroughly explored. The present study aimed to develop a novel prognostic model based on PANoptosis-related genes in CRC.
    Methods: We initially included transcriptome data of 404 CRC samples from The Cancer Genome Atlas (TCGA) cohort and identified differentially expressed genes related to PANoptosis. We then employed Cox, least absolute shrinkage and selection operator (LASSO) regression, and Random Forest methods to determine the prognostic value and constructed a PANoptosis prognostic model, followed by the validation on both internal (TCGA) and external datasets [Nanjing Colorectal Cancer (NJCRC) and Gene Expression Omnibus (GEO), n=635]. We performed immune infiltration analysis and gene set enrichment analysis to reveal biological processes and pathways against differential risk score. Ultimately, we carried out drug sensitivity analysis to predict the response of CRC patients to diverse treatment strategies.
    Results: We constructed a predictive model based on four PANoptosis-related genes (TIMP1, CDKN2A, CAMK2B, and TLR3), with a high performance [area under the curve (AUC)1-year =0.702, AUC3-year =0.725, AUC5-year =0.668] and being an independent prognostic factor in predicting the prognosis of CRC patients. Notably, colorectal tumor with high PANoptosis risk score performed higher levels of macrophage infiltration and immune scores, but a greater reduction of Tumor Microenvironment Score (TMEscore) and DNA replication. Particularly, patients in high-risk group exhibited higher sensitivity to fluorouracil, oxaliplatin and lapatinib compared to the low-risk group.
    Conclusions: This study highlights the prognostic potential of PANoptosis-related features in CRC, demonstrating their role as key biomarkers significantly associated with patient survival and aiding in the identification of high-risk patients, thereby advancing immunotherapy approaches.
    Keywords:  Colorectal cancer (CRC); PANoptosis; prognosis
    DOI:  https://doi.org/10.21037/jgo-24-245
  10. Nat Commun. 2024 Nov 21. 15(1): 10087
    DUSP6 regulates Notch1 signalling in colorectal cancer.
    Chin Wen Png, Madhushanee Weerasooriya, Heng Li, Xiaowen Hou, Fiona Yayuan Teo, Shiying Huang, Zheng Ser, Franklin Yau Kok Weng, Malini Rethnam, Gloryn Chia, Radoslaw M Sobota, Choon Seng Chong, Ker-Kan Tan, Yongliang Zhang.
      Notch1 plays various roles in cancer development, and Notch1-induced transactivation is controlled by phosphorylation of its cleaved intracellular domain. However, it is unclear whether there are phosphatases capable of dephosphorylating the cleaved Notch1 transmembrane/intracellular region (NTM) to regulate its function. Here, we show that DUSP6 can function as a phosphatase for Notch1, thereby regulating NTM stability and transcriptional activity, thus influencing colorectal cancer (CRC) development. In human CRC cells, elevated DUSP6 expression correlates with increased NTM levels, leading to enhanced CRC cell proliferation both in vitro and in vivo. High tumoral DUSP6 protein expression is associated with poorer overall CRC patient survival. In mice, DUSP6 deficiency results in reduced CRC development. Mechanistically, DUSP6 dephosphorylates phospho-Y2116, which in turn reduces NTM ubiquitination, leading to increased NTM stability and transcriptional activity. As a result, the expression of Notch1-targeted proliferation genes is increased to promote tumour cell growth.
    DOI:  https://doi.org/10.1038/s41467-024-54383-y
  11. Adv Exp Med Biol. 2024 Nov 21.
    Dietary Lipids and Their Metabolism in the Midgut.
    Pierre Delamotte, Jacques Montagne.
      Animals use dietary lipids to sustain their growth and survival. Insects can synthesize fatty acids (FAs) and are autotroph for a number of lipids, but auxotroph for specific lipids classes (e.g. sterols, polyunsaturated FAs). Once ingested, lipids are hydrolysed in the intestinal lumen and taken up into intestinal cells within specific regions of the insect digestive tract. These lipids can be either stored in the intestinal cells or exported through the haemolymph circulation to specific organs. In this chapter, we describe the various lipids provided by insect diets, their extracellular hydrolysis in the gut lumen and their intake and metabolic fate in the intestinal cells. This chapter emphasizes the critical role of the digestive tract and its regionalization in processing dietary lipids prior to their transfer to the requiring tissues.
    Keywords:  Columnar cells; Digestion; Emulsifier; Hydrolysis; Lipase; Lipid transporter; Membrane; Microbiota
    DOI:  https://doi.org/10.1007/5584_2024_835
  12. World J Gastrointest Oncol. 2024 Nov 15. 16(11): 4354-4368
    Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer.
    Run-Zhi Deng, Xin Zheng, Zhong-Lei Lu, Ming Yuan, Qi-Chang Meng, Tao Wu, Yu Tian.
      The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role - immune checkpoints - and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
    Keywords:  Colorectal cancer; Colorectal cancer stem cells; Review; Tumor immune microenvironment; Tumor metastasis
    DOI:  https://doi.org/10.4251/wjgo.v16.i11.4354
  13. J Gastrointest Oncol. 2024 Oct 31. 15(5): 2353-2357
    The role of negative hyperselection in metastatic colorectal cancer.
    Jingran Ji, Marwan Fakih.
      
    Keywords:  Negative hyperselection; RAS wild type (RAS WT); cetuximab (Cmab); metastatic colorectal cancer (mCRC); panitumumab (Pmab)
    DOI:  https://doi.org/10.21037/jgo-24-376
  14. Sci Rep. 2024 Nov 20. 14(1): 28762
    Cell hiding in colorectal cancer: correlation with response to chemotherapy in vitro and in vivo.
    I Druzhkova, A Potapov, N Ignatova, M Bugrova, I Shchechkin, M Lukina, L Shimolina, E Kolesnikova, M Shirmanova, E Zagaynova.
      Resistance to chemotherapy remains the main challenge for cancer treatment. One of the mechanisms of tumor escape from cytotoxic agents could be the formation of cell-in-cell (CIC) structures, in which the outer cell protects the inner cell from unfavorable environment. Such structures have been found in many tumor types, however, their link to chemosensitivity is elusive. Here, we tested whether the CIC structures can promote resistance of colorectal cancer cells to chemotherapy. To identify CIC structures in cell cultures and in tumor xenografts, both transmission electron microscopy and confocal fluorescence microscopy of live and fixed cells as well as tissue slices and histopathology were used. Cytogenetic analysis was performed to detect chromosome instability associated with the drug resistance. It was found that in the five colorectal cancer cell lines intrinsic chemoresistance positively correlated with the ability of cells to spontaneously form CIC structures. Cultured cells treated with oxaliplatin and Irinotecan and tumor xenografts treated with FOLFOX or FOLFIRI regimens displayed an increased number of CICs after the treatment. The release of the inner cell from CIC structure was observed after removal of the drug. The number of CICs in the cell lines and tumors with acquired resistance to oxaliplatin was higher than in the drug-naive counterparts. The development of chemoresistance was also accompanied by the changes in the cell's ploidy. These preliminary data clearly demonstrate the associations of CIC structures with chemoresistance of colorectal cancer in cultured cells and tumor xenografts and show the prospect of further clinical validation of CICs as a potential prognostic marker for treatment efficiency.
    Keywords:  CIC; Cell-in-cell structures; Chemoresistance; Colorectal cancer; Entosis
    DOI:  https://doi.org/10.1038/s41598-024-79948-1
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