bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–11–12
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila.
  2. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
  3. Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon.
  4. Single-cell isolation from full-thickness human intestinal tissue resections for single-cell RNA sequencing.
  5. Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+ T regulatory cells.
  6. CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.
  7. Dysregulation of the environmental sensor Aryl hydrocarbon receptor affects differentiation of human colon organoids.
  8. Disruption of hypoxia inducible factor-2α in neutrophils decreases colitis-associated colon cancer.
  9. Detection and clinical significance of CEACAM5 methylation in colorectal cancer patients.
  10. TEAD Inhibition Overcomes YAP1/TAZ-driven Primary and Acquired Resistance to KRASG12C Inhibitors.
  1. Cell Rep. 2023 Nov 02. pii: S2211-1247(23)01382-7. [Epub ahead of print]42(11): 113370
    Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila.
    Maria Quintero, Erdem Bangi.
      Most epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types ensures precise regulation of stem cell behavior and cell fate decisions. These cell-cell interactions are often disrupted during tumorigenesis, but mechanisms by which they are co-opted to support tumor growth in different genetic contexts are poorly understood. Here, we introduce PromoterSwitch, a genetic platform we established to generate large, transformed clones derived from individual adult Drosophila intestinal stem/progenitor cells. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes disrupt cell fate decisions within transformed tissue and result in the emergence of abnormal cell fates. We also show that transformed enteroendocrine cells, a differentiated, hormone-secreting cell lineage, support tumor growth by regulating intestinal stem cell proliferation through multiple genotype-dependent mechanisms, which represent potential vulnerabilities that could be exploited for therapy.
    Keywords:  CP: Cancer; Drosophila; cancer model; cell signaling; cell-cell communication; colon cancer; enteroendocrine cell; intestinal stem cell; tumorigenesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113370
  2. JCI Insight. 2023 Nov 08. pii: e167874. [Epub ahead of print]8(21):
    SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
    Sha-Sha Hu, Yue Han, Tian-Yuan Tan, Hui Chen, Jia-Wen Gao, Lan Wang, Min-Hui Yang, Li Zhao, Yi-Qing Wang, Yan-Qing Ding, Shuang Wang.
      Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
    Keywords:  Amino acid metabolism; Colorectal cancer; Drug therapy; Gastroenterology; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.167874
  3. Cell Stem Cell. 2023 Nov 02. pii: S1934-5909(23)00364-8. [Epub ahead of print]30(11): 1434-1451.e9
    Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon.
    Jorge O Múnera, Daniel O Kechele, Carine Bouffi, Na Qu, Ran Jing, Pritiprasanna Maity, Jacob R Enriquez, Lu Han, Ian Campbell, Maxime M Mahe, Heather A McCauley, Xinghao Zhang, Nambirajan Sundaram, Jonathan R Hudson, Adrian Zarsozo-Lacoste, Suman Pradhan, Kentaro Tominaga, J Guillermo Sanchez, Alison A Weiss, Praneet Chatuvedi, Jason R Spence, Mariam Hachimi, Trista North, George Q Daley, Christopher N Mayhew, Yueh-Chiang Hu, Takanori Takebe, Michael A Helmrath, James M Wells.
      Most organs have tissue-resident immune cells. Human organoids lack these immune cells, which limits their utility in modeling many normal and disease processes. Here, we describe that pluripotent stem cell-derived human colonic organoids (HCOs) co-develop a diverse population of immune cells, including hemogenic endothelium (HE)-like cells and erythromyeloid progenitors that undergo stereotypical steps in differentiation, resulting in the generation of functional macrophages. HCO macrophages acquired a transcriptional signature resembling human fetal small and large intestine tissue-resident macrophages. HCO macrophages modulate cytokine secretion in response to pro- and anti-inflammatory signals and were able to phagocytose and mount a robust response to pathogenic bacteria. When transplanted into mice, HCO macrophages were maintained within the colonic organoid tissue, established a close association with the colonic epithelium, and were not displaced by the host bone-marrow-derived macrophages. These studies suggest that HE in HCOs gives rise to multipotent hematopoietic progenitors and functional tissue-resident macrophages.
    Keywords:  endothelial-to-hematopoietic transition; hemogenic endothelium; human colonic organoids; tissue-resident macrophages
    DOI:  https://doi.org/10.1016/j.stem.2023.10.002
  4. STAR Protoc. 2023 Nov 03. pii: S2666-1667(23)00653-6. [Epub ahead of print]4(4): 102686
    Single-cell isolation from full-thickness human intestinal tissue resections for single-cell RNA sequencing.
    Gail A West, Shuai Zhao, Quang Tam Nguyen, Stephen M Christensen, Ilyssa O Gordon, Stefan D Holubar, Kellie M Kravarik, Claudio Fiocchi, Pranab K Mukherjee, Florian Rieder.
      Single-cell isolation techniques allow the investigation of physical and functional relationships between individual cells within a complex cell population. Here, we present a protocol for single-cell isolation from full-thickness intestinal tissue resections. We describe steps for pre-processing specimens, isolation of lamina propria and muscular layers, and red blood cell lysis. We then detail fixation of isolated cells and assessment of cell quality. The resulting cell suspension can be subjected to RNA sequencing on the 10× Chromium platform. For complete details on the use and execution of this protocol, please refer to Mukherjee et al.1.
    Keywords:  Cell isolation; Cell separation/fractionation; RNA-seq; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2023.102686
  5. J Mol Cell Biol. 2023 Nov 03. pii: mjad067. [Epub ahead of print]
    Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+ T regulatory cells.
    Yixian Guo, Feng Xie, Xu Liu, Shouyu Ke, Jieqiong Chen, Yi Zhao, Ning Li, Zeyu Wang, Gang Yi, Yanying Shen, Dan Li, Chunchao Zhu, Zizhen Zhang, Gang Zhao, Hong Lu, Bin Li, Wenyi Zhao.
      Enrichment of regulatory T cells (Tregs) in the tumour microenvironment (TME) has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors. C-C motif chemokine receptor 8 (CCR8), a marker of activated suppressive Tregs, has a significant impact on the functions of Tregs in the TME. However, the regulatory mechanism of CCR8 in Tregs remains unclear. Here, we reveal that a high level of TNF-α in the colorectal cancer (CRC) microenvironment upregulates CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor. Furthermore, in both anti-PD1-responsive and anti-PD1-unresponsive tumour models, PD1 blockade induced CCR8+ Treg infiltration. In both models, Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy. Finally, we identified that TNFR2+CCR8+ Tregs but not total Tregs are positively correlated with adverse prognosis in CRC and gastric cancer. Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.
    Keywords:  CCR8; TNFR2; colorectal cancer; regulatory T cells
    DOI:  https://doi.org/10.1093/jmcb/mjad067
  6. Dev Cell. 2023 Nov 02. pii: S1534-5807(23)00525-7. [Epub ahead of print]
    CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer.
    Zhenzhen Wu, Xuanxuan Zhang, Yunhe An, Kaiyue Ma, Ruixin Xue, Gaoqi Ye, Junfeng Du, Zhiyong Chen, Zijing Zhu, Guizhi Shi, Xiang Ding, Meng Wan, Bing Jiang, Peng Zhang, Jinbo Liu, Pengcheng Bu.
      CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits β-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated β-catenin translocation inactivates Wnt(Wingless and INT-1)/β-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/β-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.
    Keywords:  ATRA; CLMP; CRC; CYP26A1; β-catenin
    DOI:  https://doi.org/10.1016/j.devcel.2023.10.006
  7. Cell Mol Gastroenterol Hepatol. 2023 Nov 07. pii: S2352-345X(23)00197-2. [Epub ahead of print]
    Dysregulation of the environmental sensor Aryl hydrocarbon receptor affects differentiation of human colon organoids.
    Anke Liebert, Michael Shapiro, Muralidhara Rao Maradana, Ying Li, Nicholas Powell, Matthias Zilbauer, Brigitta Stockinger.
      
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.11.002
  8. Am J Physiol Gastrointest Liver Physiol. 2023 Nov 07.
    Disruption of hypoxia inducible factor-2α in neutrophils decreases colitis-associated colon cancer.
    Rashi Singhal, Nikhil Kumar Kotla, Sumeet Solanki, Wesley Huang, Hannah N Bell, Marwa O Elderany, Cristina Castillo, Yatrik M Shah.
      Neutrophils are abundant immune cells in the colon tumor microenvironment. Studies have shown that neutrophils are recruited into hypoxic foci in colon cancer. However, the impact of hypoxia signaling on neutrophil function and its involvement in colon tumorigenesis remain unclear. To address this, we generated mice with a deletion of hypoxia (HIF)-1α or HIF-2α in neutrophils driven by the MRP8Cre (HIF-1αΔNeu) or (HIF-2αΔNeu) and littermate controls. In an azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colon cancer, the disruption of neutrophils-HIF-1α did not result in any significant changes in body weight, colon length, tumor size, proliferation, or burden. However, the disruption of HIF-2α in neutrophils led to a slight increase in body weight, a significant decrease in the number of tumors, and a reduction in tumor size and volume compared to their littermate controls. Histological analysis of colon tissue from mice with HIF-2α-deficient neutrophils revealed notable reductions in proliferation as compared to control mice. Additionally, we observed reduced levels of pro-inflammatory cytokines, such as TNF-α and IL-1β, in neutrophil-specific HIF-2α deficient mice in both the tumor tissue as well as the neutrophils. Importantly, it is worth noting that the reduced tumorigenesis associated with HIF-2α deficiency in neutrophils was not evident in already established syngeneic tumors or a DSS-induced inflammation model, indicating a potential role of HIF-2α specifically in colon tumorigenesis. In conclusion, we found that the loss of neutrophil-specific HIF-2α slows colon tumor growth and progression by reducing the levels of inflammatory mediators.
    Keywords:  Neutrophil; colorectal cancer; hypoxia; inflammation
    DOI:  https://doi.org/10.1152/ajpgi.00182.2023
  9. Cancer Sci. 2023 Nov 09.
    Detection and clinical significance of CEACAM5 methylation in colorectal cancer patients.
    Sheng-Chieh Huang, Shih-Ching Chang, Tsai-Tsen Liao, Muh-Hwa Yang.
      Colorectal cancer (CRC) is a globally common cancer, and the serum carcinoembryonic antigen (sCEA) is widely applied as a diagnostic and prognostic tumor marker in CRC. This study aimed to elucidate the mechanism of CEA expression and corresponding clinical features to improve prognostic assessments. In CRC cells, hypomethylation of the CEACAM5 promoter enhanced CEA expression in HCT116 and HT29 cells with 5-aza-2'-deoxycytidine (5-Aza-dC) treatment. Our clinical data indicated that 64.7% (101/156) of CRC patients had an sCEA level above the normal range, and 76.2% (77/101) of those patients showed a lower average CpG methylation level of the CEACAM5 promoter. The methylation analysis showed that both CRC cell lines and patient samples shared the same critical methylation CpG regions at -200 to -500 and -1000 to -1400 bp of the CEACAM5 promoter. Patients with hypermethylation of the CEACAM5 promoter showed features of a BRAF mutation, TGFB2 mutation, microsatellite instability-high, and preference for right-sided colorectal cancer and peritoneal seeding presentation that had a similar clinical character to the consensus molecular subtype 1 (CMS1) of colorectal cancer. Additionally, hypermethylation of the CEACAM5 promoter combined with evaluated sCEA demonstrated the worst survival among the patients. Therefore, the methylation status of the CEACAM5 promoter also served as an effective biomarker for assessing disease prognosis. Results indicated that DNA methylation is a major regulatory mechanism for CEA expression in colorectal cancer. Moreover, our data also highlighted that patients in a subgroup who escaped from inactivation by DNA methylation had distinct clinical and pathological features and the worst survival.
    Keywords:   CEACAM5 ; CEA; CEA regulation; DNA methylation; colorectal cancer
    DOI:  https://doi.org/10.1111/cas.16012
  10. Cancer Res. 2023 Nov 07.
    TEAD Inhibition Overcomes YAP1/TAZ-driven Primary and Acquired Resistance to KRASG12C Inhibitors.
    A Cole Edwards, Clint A Stalnecker, Alexis Jean Morales, Khalilah E Taylor, Jennifer E Klomp, Jeffrey A Klomp, Andrew M Waters, Niranjan Sudhakar, Jill Hallin, Tracy T Tang, Peter Olson, Leonard Post, James G Christensen, Adrienne D Cox, Channing J Der.
      Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRASG12C mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the anti-proliferative and pro-apoptotic effects of KRASG12C inhibitor (G12Ci) treatment in KRASG12C-mutant cancer cell lines. Conversely, genetic suppression of YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor-dependent mechanisms that phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1 and MYC) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K-AKT-mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor anti-tumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the anti-tumor efficacy of KRAS-targeted therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2994
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