bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–07–23
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Three-dimensional heterotypic colorectal cancer spheroid models for evaluation of drug response.
  2. Mitochondria in colorectal cancer stem cells - a target in drug resistance.
  3. The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity.
  4. IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer.
  5. Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance.
  6. Genome wide association study identifies 4 novel risk loci for small intestinal neuroendocrine tumors including a missense mutation in LGR5.
  7. Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches.
  8. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
  9. Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
  10. Organization of the human intestine at single-cell resolution.
  1. Front Oncol. 2023 ;13 1148930
    Three-dimensional heterotypic colorectal cancer spheroid models for evaluation of drug response.
    Jia Ning Nicolette Yau, Giulia Adriani.
      Colorectal cancer (CRC) is a leading cause of death worldwide. Improved preclinical tumor models are needed to make treatment screening clinically relevant and address disease mortality. Advancements in 3D cell culture have enabled a greater recapitulation of the architecture and heterogeneity of the tumor microenvironment (TME). This has enhanced their pathophysiological relevance and enabled more accurate predictions of tumor progression and drug response in patients. An increasing number of 3D CRC spheroid models include cell populations such as cancer-associated fibroblasts (CAFs), endothelial cells (ECs), immune cells, and gut bacteria to better mimic the in vivo regulation of signaling pathways. Furthermore, cell heterogeneity within the 3D spheroid models enables the identification of new therapeutic targets to develop alternative treatments and test TME-target therapies. In this mini review, we present the advances in mimicking tumor heterogeneity in 3D CRC spheroid models by incorporating CAFs, ECs, immune cells, and gut bacteria. We introduce how, in these models, the diverse cells influence chemoresistance and tumor progression of the CRC spheroids. We also highlight important parameters evaluated during drug screening in the CRC heterocellular spheroids.
    Keywords:  cancer associated fibroblast (CAF); colorectal cancer; drug screening; endothelial cell; gut microbiota; heterotypic 3D model; spheroid; tumor associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fonc.2023.1148930
  2. Cancer Drug Resist. 2023 ;6(2): 273-283
    Mitochondria in colorectal cancer stem cells - a target in drug resistance.
    Mateus de Almeida Rainho, Priscyanne Barreto Siqueira, Ísis Salviano Soares de Amorim, Andre Luiz Mencalha, Alessandra Alves Thole.
      Colorectal cancer (CRC) is the third most diagnosed cancer and the second most deadly type of cancer worldwide. In late diagnosis, CRC can resist therapy regimens in which cancer stem cells (CSCs) are intimately related. CSCs are a subpopulation of tumor cells responsible for tumor initiation and maintenance, metastasis, and resistance to conventional treatments. In this scenario, colorectal cancer stem cells (CCSCs) are considered an important key for therapeutic failure and resistance. In its turn, mitochondria is an organelle involved in many mechanisms in cancer, including chemoresistance of cytotoxic drugs due to alterations in mitochondrial metabolism, apoptosis, dynamics, and mitophagy. Therefore, it is crucial to understand the mitochondrial role in CCSCs regarding CRC drug resistance. It has been shown that enhanced anti-apoptotic protein expression, mitophagy rate, and addiction to oxidative phosphorylation are the major strategies developed by CCSCs to avoid drug insults. Thus, new mitochondria-targeted drug approaches must be explored to mitigate CRC chemoresistance via the ablation of CCSCs.
    Keywords:  Cancer stem cells; colorectal cancer; drug resistance; mitochondria; mitophagy
    DOI:  https://doi.org/10.20517/cdr.2022.116
  3. Cancer Discov. 2023 Jul 20. OF1-OF18
    The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity.
    Alastair Davies, Amina Zoubeidi, Himisha Beltran, Luke A Selth.
      Lineage plasticity, a process whereby cells change their phenotype to take on a different molecular and/or histologic identity, is a key driver of cancer progression and therapy resistance. Although underlying genetic changes within the tumor can enhance lineage plasticity, it is predominantly a dynamic process controlled by transcriptional and epigenetic dysregulation. This review explores the transcriptional and epigenetic regulators of lineage plasticity and their interplay with other features of malignancy, such as dysregulated metabolism, the tumor microenvironment, and immune evasion. We also discuss strategies for the detection and treatment of highly plastic tumors.
    SIGNIFICANCE: Lineage plasticity is a hallmark of cancer and a critical facilitator of other oncogenic features such as metastasis, therapy resistance, dysregulated metabolism, and immune evasion. It is essential that the molecular mechanisms of lineage plasticity are elucidated to enable the development of strategies to effectively target this phenomenon. In this review, we describe key transcriptional and epigenetic regulators of cancer cell plasticity, in the process highlighting therapeutic approaches that may be harnessed for patient benefit.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0225
  4. Nat Commun. 2023 07 17. 14(1): 4251
    IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer.
    E Koncina, M Nurmik, V I Pozdeev, C Gilson, M Tsenkova, R Begaj, S Stang, A Gaigneaux, C Weindorfer, F Rodriguez, M Schmoetten, E Klein, J Karta, V S Atanasova, K Grzyb, P Ullmann, R Halder, M Hengstschläger, J Graas, V Augendre, Y E Karapetyan, L Kerger, N Zuegel, A Skupin, S Haan, J Meiser, H Dolznig, E Letellier.
      Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.
    DOI:  https://doi.org/10.1038/s41467-023-39953-w
  5. Stem Cell Rev Rep. 2023 Jul 21.
    Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance.
    Qiuzhi Gao, Yixiang Zhan, Li Sun, Wei Zhu.
      Although there has been some progress in the efficacy of anti-cancer drugs, drug resistance remains challenging. Cancer stem cells (CSCs) are self-renewing and differentiate into cancer tissues with tumor heterogeneity. CSCs are associated with the progression of breast, colon, and lung cancers. Hence, recent studies have focused on the role of CSCs in resistance to anti-cancer drugs. Increasing evidence suggests that CSCs interact with components of the tumor microenvironment (TME), such as vascular and immune cells, as well as various cytokines, and are regulated by multiple signaling pathways, thereby promoting drug resistance in various cancers. Therefore, it is important to clarify the mechanisms underlying the crosstalk between CSCs and the TME for the development of targeted anti-cancer therapies.
    Keywords:  Cancer stem cells; Drug resistance; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12015-023-10593-3
  6. Gastroenterology. 2023 Jul 13. pii: S0016-5085(23)04769-8. [Epub ahead of print]
    Genome wide association study identifies 4 novel risk loci for small intestinal neuroendocrine tumors including a missense mutation in LGR5.
    Anil K Giri, Mervi Aavikko, Linnea Wartiovaara, Toni Lemmetyinen, Juha Karjalainen, Juha Mehtonen, Kimmo Palin, Niko Välimäki, Max Tamlander, Riikka Saikkonen, Auli Karhu, Ekaterina Morgunova, Benjamin Sun, Heiko Runz, Priit Palta, Shuang Luo, Heikki Joensuu, Tomi P Mäkelä, Iiro Kostiainen, Camilla Schalin-Jäntti, FinnGen, Aarno Palotie, Lauri A Aaltonen, Saara Ollila, Mark J Daly.
       BACKGROUND AND AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease whose incidence has increased over the last 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here, we report the results of the largest genome-wide association study (GWAS) of SI-NETs performed to date with 405 cases and 614,666 controls.
    METHODS: We used samples from 307 SI-NET patients and 287,137 controls in the FinnGen study for the identification of SI-NET risk-associated genetic variants. We also metanalysed the results with summary statistics from the UK Biobank (n=98 SI-NET cases and n=327,529 controls).
    RESULTS: We identified 6 genome-wide significant (p<5x10-8) loci associated with SI-NET risk, of which 4 (near SEMA6A, LGR5, CDKAL1, and FERMT2) are novel and 2 (near LTA4H-ELK and in KIF16B) have been previously reported. Interestingly, the top hit (rs200138614, p=1.80x10-19) is a missense variant (p.Cys712Phe) in the LGR5 gene, a bona fide marker of adult intestinal stem cells and a potentiator of canonical WNT signaling. The association was validated in an independent Finnish collection of 70 SI-NET patients, as well as in the UK Biobank exome sequence data (n=92 cases and n=392,814 controls). Overexpression of LGR5 p.Cys712Phe in intestinal organoids abolished the ability of R-Spondin1 to support organoid growth, indicating that the mutation perturbed R-Spondin-LGR5 signaling.
    CONCLUSION: Our study is the largest GWAS study to date on SI-NETs and reports 4 new associated GWAS loci, including a novel missense mutation (rs200138614, p.Cys712Phe) in LGR5, a canonical marker of adult intestinal stem cells.
    Keywords:  CDKAL1; FERMT2; FinnGen; SEMA6A; SI-NET
    DOI:  https://doi.org/10.1053/j.gastro.2023.06.031
  7. J Exp Clin Cancer Res. 2023 Jul 22. 42(1): 177
    Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches.
    Yaxian Wang, Xinyang Zhong, Xuefeng He, Zijuan Hu, Huixia Huang, Jiayu Chen, Keji Chen, Senlin Zhao, Ping Wei, Dawei Li.
      Colorectal cancer liver metastasis (CRLM) is one of the leading causes of death among patients with colorectal cancer (CRC). Although immunotherapy has demonstrated encouraging outcomes in CRC, its benefits are minimal in CRLM. The complex immune landscape of the hepatic tumour microenvironment is essential for the development of a premetastatic niche and for the colonisation and metastasis of CRC cells; thus, an in-depth understanding of these mechanisms can provide effective immunotherapeutic targets for CRLM. This review summarises recent studies on the immune landscape of the tumour microenvironment of CRLM and highlights therapeutic prospects for targeting the suppressive immune microenvironment of CRLM.
    Keywords:  Colorectal cancer liver metastasis; Immune landscape; Immunotherapy; Premetastatic niche; Tumour microenvironment
    DOI:  https://doi.org/10.1186/s13046-023-02729-7
  8. Nature. 2023 Jul 19.
    Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
    Yogesh Goyal, Gianna T Busch, Maalavika Pillai, Jingxin Li, Ryan H Boe, Emanuelle I Grody, Manoj Chelvanambi, Ian P Dardani, Benjamin Emert, Nicholas Bodkin, Jonas Braun, Dylan Fingerman, Amanpreet Kaur, Naveen Jain, Pavithran T Ravindran, Ian A Mellis, Karun Kiani, Gretchen M Alicea, Mitchell E Fane, Syeda Subia Ahmed, Haiyin Li, Yeqing Chen, Cedric Chai, Jessica Kaster, Russell G Witt, Rossana Lazcano, Davis R Ingram, Sarah B Johnson, Khalida Wani, Margaret C Dunagin, Alexander J Lazar, Ashani T Weeraratna, Jennifer A Wargo, Meenhard Herlyn, Arjun Raj.
      Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
    DOI:  https://doi.org/10.1038/s41586-023-06342-8
  9. Nat Commun. 2023 Jul 19. 14(1): 4342
    Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
    Alfredo Erazo-Oliveras, Mónica Muñoz-Vega, Mohamed Mlih, Venkataramana Thiriveedi, Michael L Salinas, Jaileen M Rivera-Rodríguez, Eunjoo Kim, Rachel C Wright, Xiaoli Wang, Kerstin K Landrock, Jennifer S Goldsby, Destiny A Mullens, Jatin Roper, Jason Karpac, Robert S Chapkin.
      Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a link between oncogenic APC, loss of plasma membrane homeostasis and CRC development.
    DOI:  https://doi.org/10.1038/s41467-023-39640-w
  10. Nature. 2023 Jul;619(7970): 572-584
    Organization of the human intestine at single-cell resolution.
    John W Hickey, Winston R Becker, Stephanie A Nevins, Aaron Horning, Almudena Espin Perez, Chenchen Zhu, Bokai Zhu, Bei Wei, Roxanne Chiu, Derek C Chen, Daniel L Cotter, Edward D Esplin, Annika K Weimer, Chiara Caraccio, Vishal Venkataraaman, Christian M Schürch, Sarah Black, Maria Brbić, Kaidi Cao, Shuxiao Chen, Weiruo Zhang, Emma Monte, Nancy R Zhang, Zongming Ma, Jure Leskovec, Zhengyan Zhang, Shin Lin, Teri Longacre, Sylvia K Plevritis, Yiing Lin, Garry P Nolan, William J Greenleaf, Michael Snyder.
      The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.
    DOI:  https://doi.org/10.1038/s41586-023-05915-x
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