bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–01–07
nineteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Protein arginine methyltransferase 1 is required for the maintenance of adult small intestinal and colonic epithelial cell homeostasis.
  2. Sleeping Beauty transposon mutagenesis in mouse intestinal organoids identifies genes involved in tumor progression and metastasis.
  3. KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.
  4. The olfactory receptor Olfr78 promotes differentiation of enterochromaffin cells in the mouse colon.
  5. Paneth-like cells produced from OLFM4+ stem cells support OLFM4+ stem cell growth in advanced colorectal cancer.
  6. p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome.
  7. Identification of colorectal cancer cell stemness from single-cell RNA sequencing.
  8. Hallmarks of stemness in mammalian tissues.
  9. Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells.
  10. Single-cell RNA sequencing reveals that the immunosuppression landscape induced by chronic stress promotes colorectal cancer metastasis.
  11. Transverse colon primary tumor location as a biomarker in metastatic colorectal cancer: A pooled analysis of CCTG/AGITG CO.17 and CO.20 randomized clinical trials.
  12. Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
  13. Role of YAP Signaling in Regulation of Programmed Cell Death and Drug Resistance in Cancer.
  14. Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2.
  15. Dietary cystine restriction increases the proliferative capacity of the small intestine of mice.
  16. NEIL1 drives the initiation of colorectal cancer through transcriptional regulation of COL17A1.
  17. Gene signatures derived from transcriptomic-causal networks stratified colorectal cancer patients for effective targeted therapy.
  18. FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.
  19. Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.
  1. Int J Biol Sci. 2024 ;20(2): 554-568
    Protein arginine methyltransferase 1 is required for the maintenance of adult small intestinal and colonic epithelial cell homeostasis.
    Zhaoyi Peng, Lingyu Bao, Bingyin Shi, Yun-Bo Shi.
      The vertebrate adult intestinal epithelium has a high self-renewal rate driven by intestinal stem cells (ISCs) in the crypts, which play central roles in maintaining intestinal integrity and homeostasis. However, the underlying mechanisms remain elusive. Here we showed that protein arginine methyltransferase 1 (PRMT1), a major arginine methyltransferase that can also function as a transcription co-activator, was highly expressed in the proliferating cells of adult mouse intestinal crypts. Intestinal epithelium-specific knockout of PRMT1, which ablates PRMT1 gene starting during embryogenesis, caused distinct, region-specific effects on small intestine and colon: increasing and decreasing the goblet cell number in the small intestinal and colonic crypts, respectively, leading to elongation of the crypts in small intestine but not colon, while increasing crypt cell proliferation in both regions. We further generated a tamoxifen-inducible intestinal epithelium-specific PRMT1 knockout mouse model and found that tamoxifen-induced knockout of PRMT1 in the adult mice resulted in the same region-specific intestinal phenotypes. Thus, our studies have for the first time revealed that the epigenetic enzyme PRMT1 has distinct, region-specific roles in the maintenance of intestinal epithelial architecture and homeostasis, although PRMT1 may influence intestinal development.
    Keywords:  Arginine methylation; Epithelial homeostasis; Intestine; Self-renewal; Stem cell; methyltransferase
    DOI:  https://doi.org/10.7150/ijbs.89958
  2. Cancer Gene Ther. 2024 Jan 04.
    Sleeping Beauty transposon mutagenesis in mouse intestinal organoids identifies genes involved in tumor progression and metastasis.
    Naoko Iida, Yukari Muranaka, Jun Won Park, Shigeki Sekine, Neal G Copeland, Nancy A Jenkins, Yuichi Shiraishi, Masanobu Oshima, Haruna Takeda.
      To identify genes important for colorectal cancer (CRC) development and metastasis, we established a new metastatic mouse organoid model using Sleeping Beauty (SB) transposon mutagenesis. Intestinal organoids derived from mice carrying actively mobilizing SB transposons, an activating KrasG12D, and an inactivating ApcΔ716 allele, were transplanted to immunodeficient mice. While 66.7% of mice developed primary tumors, 7.6% also developed metastatic tumors. Analysis of SB insertion sites in tumors identified numerous candidate cancer genes (CCGs) identified previously in intestinal SB screens performed in vivo, in addition to new CCGs, such as Slit2 and Atxn1. Metastatic tumors from the same mouse were clonally related to each other and to primary tumors, as evidenced by the transposon insertion site. To provide functional validation, we knocked out Slit2, Atxn1, and Cdkn2a in mouse tumor organoids and transplanted to mice. Tumor development was promoted when these gene were knocked out, demonstrating that these are potent tumor suppressors. Cdkn2a knockout cells also metastasized to the liver in 100% of the mice, demonstrating that Cdkn2a loss confers metastatic ability. Our organoid model thus provides a new approach that can be used to understand the evolutionary forces driving CRC metastasis and a rich resource to uncover CCGs promoting CRC.
    DOI:  https://doi.org/10.1038/s41417-023-00723-x
  3. Nat Commun. 2024 Jan 02. 15(1): 100
    KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.
    Arafath K Najumudeen, Sigrid K Fey, Laura M Millett, Catriona A Ford, Kathryn Gilroy, Nuray Gunduz, Rachel A Ridgway, Eve Anderson, Douglas Strathdee, William Clark, Colin Nixon, Jennifer P Morton, Andrew D Campbell, Owen J Sansom.
      Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
    DOI:  https://doi.org/10.1038/s41467-023-44342-4
  4. EMBO Rep. 2023 Dec 15.
    The olfactory receptor Olfr78 promotes differentiation of enterochromaffin cells in the mouse colon.
    Gilles Dinsart, Morgane Leprovots, Anne Lefort, Frédérick Libert, Yannick Quesnel, Alex Veithen, Gilbert Vassart, Sandra Huysseune, Marc Parmentier, Marie-Isabelle Garcia.
      The gastrointestinal epithelium constitutes a chemosensory system for microbiota-derived metabolites such as short-chain fatty acids (SCFA). Here, we investigate the spatial distribution of Olfr78, one of the SCFA receptors, in the mouse intestine and study the transcriptome of colon enteroendocrine cells expressing Olfr78. The receptor is predominantly detected in the enterochromaffin and L subtypes in the proximal and distal colon, respectively. Using the Olfr78-GFP and VilCre/Olfr78flox transgenic mouse lines, we show that loss of epithelial Olfr78 results in impaired enterochromaffin cell differentiation, blocking cells in an undefined secretory lineage state. This is accompanied by a reduced defense response to bacteria in colon crypts and slight dysbiosis. Using organoid cultures, we further show that maintenance of enterochromaffin cells involves activation of the Olfr78 receptor via the SCFA ligand acetate. Taken together, our work provides evidence that Olfr78 contributes to colon homeostasis by promoting enterochromaffin cell differentiation.
    Keywords:  Enteroendocrine Cells; Odorant; Organoids; SCFA; Serotonin
    DOI:  https://doi.org/10.1038/s44319-023-00013-5
  5. Commun Biol. 2024 Jan 05. 7(1): 27
    Paneth-like cells produced from OLFM4+ stem cells support OLFM4+ stem cell growth in advanced colorectal cancer.
    Mizuho Sakahara, Takuya Okamoto, Upasna Srivastava, Yasuko Natsume, Hitomi Yamanaka, Yutaka Suzuki, Kazutaka Obama, Satoshi Nagayama, Ryoji Yao.
      Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood. Using patient-derived organoids established from patients with advanced colorectal cancer (CRC), we evaluated the potential of olfactomedin 4 (OLFM4)+ stem cells to produce a bifurcated lineage of progenies with absorptive and secretory properties. In the early phases of organoid reconstruction, OLFM4+ cells preferentially gave rise to secretory cells. Additionally, we found that Paneth-like cells, which do not exist in the normal colon, were induced in response to Notch signaling inhibition. Video recordings of single OLFM4+ cells revealed that organoids containing Paneth-like cells were effectively propagated and that their selective ablation led to organoid collapse. In tumor tissues, Paneth-like cells were identified only in the region where tumor cells lost cell adhesion. These findings indicate that Paneth-like cells are directly produced by OLFM4+ stem cells and that their interaction contributes to tumor formation by providing niche factors. This study reveals the importance of the cell fate specification program for building a complete tumor cellular ecosystem, which might be targeted with novel therapeutics.
    DOI:  https://doi.org/10.1038/s42003-023-05504-8
  6. Nat Commun. 2024 Jan 02. 15(1): 137
    p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome.
    Jianming Wang, Chun-Yuan Chang, Xue Yang, Fan Zhou, Juan Liu, Jill Bargonetti, Lanjing Zhang, Ping Xie, Zhaohui Feng, Wenwei Hu.
      Radiation-induced gastrointestinal syndrome is a major complication and limiting factor for radiotherapy. Tumor suppressor p53 has a protective role in radiation-induced gastrointestinal toxicity. However, its underlying mechanism remains unclear. Here we report that regulating the IL12-p40/MHC class II signaling pathway is a critical mechanism by which p53 protects against radiation-induced gastrointestinal syndrome. p53 inhibits the expression of inflammatory cytokine IL12-p40, which in turn suppresses the expression of MHC class II on intestinal epithelial cells to suppress T cell activation and inflammation post-irradiation that causes intestinal stem cell damage. Anti-IL12-p40 neutralizing antibody inhibits inflammation and rescues the defects in intestinal epithelial regeneration post-irradiation in p53-deficient mice and prolongs mouse survival. These results uncover that the IL12-p40/MHC class II signaling mediates the essential role of p53 in ensuring intestinal stem cell function and proper immune reaction in response to radiation to protect mucosal epithelium, and suggest a potential therapeutic strategy to protect against radiation-induced gastrointestinal syndrome.
    DOI:  https://doi.org/10.1038/s41467-023-44390-w
  7. Mol Cancer Res. 2023 Dec 29.
    Identification of colorectal cancer cell stemness from single-cell RNA sequencing.
    Kangyu Lin, Saikat Chowdhury, Mohammad A Zeineddine, Fadl A Zeineddine, Nicholas J Hornstein, Oscar E Villarreal, Dipen M Maru, Cara L Haymaker, Jean-Nicolas Vauthey, George J Chang, Elena Bogatenkova, David Menter, Scott Kopetz, John Paul Shen.
      Cancer stem cells (CSCs) play a critical role in metastasis, relapse, and therapy resistance in colorectal cancer. While characterization of the normal lineage of cell development in the intestine has led to the identification of many genes involved in the induction and maintenance of pluripotency, recent studies suggest significant heterogeneity in CSC populations. Moreover, while many canonical colorectal cancer CSC marker genes have been identified, the ability to use these classical markers to annotate stemness at the single-cell level is limited. In this study, we performed single-cell RNA sequencing on a cohort of 6 primary colon, 9 liver metastatic tumors, and 11 normal (non-tumor) controls to identify colorectal CSCs at the single-cell level. Finding poor alignment of the 11 genes most used to identify colorectal CSC, we instead extracted a single-cell stemness signature (SCS_sig) that robustly identified 'gold-standard' colorectal CSCs that expressed all marker genes. Using this SCS_sig to quantify stemness, we found that while normal epithelial cells show a bimodal distribution, indicating distinct stem and differentiated states, in tumor epithelial cells stemness is a continuum, suggesting greater plasticity in these cells. The SCS_sig score was quite variable between different tumors, reflective of the known transcriptomic heterogeneity of CRC. Notably, patients with higher SCS_sig scores had significantly shorter disease-free survival time after curative intent surgical resection, suggesting stemness is associated with relapse. Implications: This study reveals significant heterogeneity of expression of genes commonly used to identify colorectal CSCs, and identifies a novel stemness signature to identify these cells from scRNAseq data.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-23-0468
  8. Cell Stem Cell. 2024 Jan 04. pii: S1934-5909(23)00436-8. [Epub ahead of print]31(1): 7-24
    Hallmarks of stemness in mammalian tissues.
    Joep Beumer, Hans Clevers.
      All adult tissues experience wear and tear. Most tissues can compensate for cell loss through the activity of resident stem cells. Although the cellular maintenance strategies vary greatly between different adult (read: postnatal) tissues, the function of stem cells is best defined by their capacity to replace lost tissue through division. We discuss a set of six complementary hallmarks that are key enabling features of this basic function. These include longevity and self-renewal, multipotency, transplantability, plasticity, dependence on niche signals, and maintenance of genome integrity. We discuss these hallmarks in the context of some of the best-understood adult stem cell niches.
    Keywords:  adult stem cells; hallmarks; lineage tracing; longevity; niche; organoids; plasticity; regeneration
    DOI:  https://doi.org/10.1016/j.stem.2023.12.006
  9. Front Immunol. 2023 ;14 1302354
    Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells.
    Karla E G Soto, Liliana R Loureiro, Tabea Bartsch, Claudia Arndt, Alexandra Kegler, Nicola Mitwasi, Laura Drewitz, Lydia Hoffmann, Haidy A Saleh, Eugenia Crespo, Maria Mehnert, Cansu Daglar, Hinrich Abken, Frank Momburg, Michael Bachmann, Anja Feldmann.
      Despite the success of chimeric antigen receptor (CAR) T-cells especially for treating hematological malignancies, critical drawbacks, such as "on-target, off-tumor" toxicities, need to be addressed to improve safety in translating to clinical application. This is especially true, when targeting tumor-associated antigens (TAAs) that are not exclusively expressed by solid tumors but also on hea9lthy tissues. To improve the safety profile, we developed switchable adaptor CAR systems including the RevCAR system. RevCAR T-cells are activated by cross-linking of bifunctional adaptor molecules termed target modules (RevTM). In a further development, we established a Dual-RevCAR system for an AND-gated combinatorial targeting by splitting the stimulatory and co-stimulatory signals of the RevCAR T-cells on two individual CARs. Examples of common markers for colorectal cancer (CRC) are the carcinoembryonic antigen (CEA) and the epithelial cell adhesion molecule (EpCAM), while these antigens are also expressed by healthy cells. Here we describe four novel structurally different RevTMs for targeting of CEA and EpCAM. All anti-CEA and anti-EpCAM RevTMs were validated and the simultaneous targeting of CEA+ and EpCAM+ cancer cells redirected specific in vitro and in vivo killing by Dual-RevCAR T-cells. In summary, we describe the development of CEA and EpCAM specific adaptor RevTMs for monospecific and AND-gated targeting of CRC cells via the RevCAR platform as an improved approach to increase tumor specificity and safety of CAR T-cell therapies.
    Keywords:  AND-gate targeting; CAR T-cells; CEA; EpCAM; colorectal cancer
    DOI:  https://doi.org/10.3389/fimmu.2023.1302354
  10. Heliyon. 2024 Jan 15. 10(1): e23552
    Single-cell RNA sequencing reveals that the immunosuppression landscape induced by chronic stress promotes colorectal cancer metastasis.
    Yingru Zhang, Ying Feng, Yiyang Zhao, Yuanyuan Feng, Mengyao Li, Wenkai Wang, Zhongya Ni, Huirong Zhu, Yan Wang.
      The high prevalence of depressive disorders in individuals with cancer and their contribution to tumour progression is a topic that is gradually gaining attention. Recent evidence has shown that there are prominent connections between immune gene variants and mood disorders. The homeostasis of the tumour immune microenvironment (TIME) and the infiltration and activation of immune cells play a very important role in the antitumour effect. In this study, we established a compound mouse model with chronic unpredictable mild stress (CUMS) and orthotopic colorectal cancer to simulate colorectal cancer (CRC) patients with depression. Using 10✕Genomics single-cell transcriptome sequencing technology, we profiled nearly 30,000 cells from tumour samples of 8 mice from the control and CUMS groups, revealed that immune cells in tumours under a chronic stress state trend toward a more immunosuppressive and exhaustive status, and described the crosstalk between the overall inflammatory environment and immunosuppressive landscape to provide mechanistic information or efficacious strategies for immune-oncology treatments in CRC with depressive disorders.
    Keywords:  Chronic stress; Colorectal cancer; Depression; Metastasis; Single-cell RNA seq; Tumour immune microenvironment
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e23552
  11. Clin Cancer Res. 2024 Jan 03.
    Transverse colon primary tumor location as a biomarker in metastatic colorectal cancer: A pooled analysis of CCTG/AGITG CO.17 and CO.20 randomized clinical trials.
    Joao Paulo Solar Vasconcelos, Nan Chen, Emma Titmuss, Dongsheng Tu, Stephanie Y Brule, Rachel Goodwin, Derek J Jonker, Timothy Price, John R Zalcberg, Malcolm J Moore, Christos S Karapetis, Lillian Siu, Jeremy Shapiro, John Simes, Sharlene Gill, Chris J O'Callaghan, Jonathan M Loree.
       PURPOSE: Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left and right-sided CRC is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC.
    EXPERIMENTAL DESIGN: Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wildtype mCRC from CO.17 and KRAS wildtype mCRC from CO.20 were analyzed according to location.
    RESULTS: 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall Survival (OS) (median, 5.9 vs. 2.1 months; HR, 0.63; 95% CI, 0.28-1.42; P=0.26) and progression-free survival (PFS) (median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared to transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone.
    CONCLUSION: Transverse mCRC has comparable prognostic and predictive features to right-sided mCRC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3275
  12. Nat Commun. 2024 Jan 02. 15(1): 79
    Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
    Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.
      How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.
    DOI:  https://doi.org/10.1038/s41467-023-44412-7
  13. Int J Biol Sci. 2024 ;20(1): 15-28
    Role of YAP Signaling in Regulation of Programmed Cell Death and Drug Resistance in Cancer.
    Wei Zhou, Adrian Lim, Mouad Edderkaoui, Arsen Osipov, Heshui Wu, Qiang Wang, Stephen Pandol.
      Although recent advances in cancer treatment significantly improved the prognosis of patients, drug resistance remains a major challenge. Targeting programmed cell death is a major approach of antitumor drug development. Deregulation of programmed cell death (PCD) contributes to resistance to a variety of cancer therapeutics. Yes-associated protein (YAP) and its paralog TAZ, the main downstream effectors of the Hippo pathway, are aberrantly activated in a variety of human malignancies. The Hippo-YAP pathway, which was originally identified in Drosophila, is well conserved in humans and plays a defining role in regulation of cell fate, tissue growth and regeneration. Activation of YAP signaling has emerged as a key mechanism involved in promoting cancer cell proliferation, metastasis, and drug resistance. Understanding the role of YAP/TAZ signaling network in PCD and drug resistance could facilitate the development of effective strategies for cancer therapeutics.
    Keywords:  Apoptosis; Autophagy; Drug resistance; Ferroptosis; Programmed cell death; YAP/TAZ
    DOI:  https://doi.org/10.7150/ijbs.83586
  14. EMBO J. 2023 Dec 20.
    Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2.
    Eva Cloots, Phaedra Guilbert, Mathias Provost, Lisa Neidhardt, Evelien Van de Velde, Farzaneh Fayazpour, Delphine De Sutter, Savvas N Savvides, Sven Eyckerman, Sophie Janssens.
      Intestinal goblet cells are secretory cells specialized in the production of mucins, and as such are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme-1β (IRE1β), a unique sensor in the unfolded protein response (UPR), which is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1β activity is tuned to mucus folding load remains unknown. We identified the disulfide isomerase and mucin chaperone AGR2 as a goblet cell-specific protein that crucially regulates IRE1β-, but not IRE1α-mediated signaling. AGR2 binding to IRE1β disrupts IRE1β oligomerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1β activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1β activation. We found that AGR2 mutants lacking their catalytic cysteine, or displaying the disease-associated mutation H117Y, were no longer able to dampen IRE1β activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1β endonuclease activity.
    Keywords:  AGR2; Goblet Cells; IRE1β; Mucus Homeostasis; Unfolded Protein Response (UPR)
    DOI:  https://doi.org/10.1038/s44318-023-00015-y
  15. PLoS One. 2024 ;19(1): e0290493
    Dietary cystine restriction increases the proliferative capacity of the small intestine of mice.
    Judith C W de Jong, Kristel S van Rooijen, Edwin C A Stigter, M Can Gülersönmez, Marcel R de Zoete, Janetta Top, Matthijs J D Baars, Yvonne Vercoulen, Folkert Kuipers, Saskia W C van Mil, Noortje Ijssennagger.
      Currently, over 88 million people are estimated to have adopted a vegan or vegetarian diet. Cysteine is a semi-essential amino acid, which availability is largely dependent on dietary intake of meat, eggs and whole grains. Vegan/vegetarian diets are therefore inherently low in cysteine. Sufficient uptake of cysteine is crucial, as it serves as substrate for protein synthesis and can be converted to taurine and glutathione. We found earlier that intermolecular cystine bridges are essential for the barrier function of the intestinal mucus layer. Therefore, we now investigate the effect of low dietary cystine on the intestine. Mice (8/group) received a high fat diet with a normal or low cystine concentration for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels or bile acid conjugation after 2 weeks of low cystine feeding. In the colon, dietary cystine restriction results in an increase in goblet cell numbers, and a borderline significant increase mucus layer thickness. Gut microbiome composition and expression of stem cell markers did not change on the low cystine diet. Remarkably, stem cell markers, as well as the proliferation marker Ki67, were increased upon cystine restriction in the small intestine. In line with this, gene set enrichment analysis indicated enrichment of Wnt signaling in the small intestine of mice on the low cystine diet, indicative of increased epithelial proliferation. In conclusion, 2 weeks of cystine restriction did not result in apparent systemic effects, but the low cystine diet increased the proliferative capacity specifically of the small intestine and induced the number of goblet cells in the colon.
    DOI:  https://doi.org/10.1371/journal.pone.0290493
  16. Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01665-0. [Epub ahead of print]43(1): 113654
    NEIL1 drives the initiation of colorectal cancer through transcriptional regulation of COL17A1.
    Jing-Hua Cao, Chen-Hui Cao, Jin-Long Lin, Si-Yu Li, Long-Jun He, Kai Han, Jie-Wei Chen, Si Li, Xin Wang, Dan Xie, Feng-Wei Wang.
      Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.
    Keywords:  COL17A1; CP: Cancer; DNA repair; NEIL1; colorectal cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.113654
  17. Res Sq. 2023 Dec 15. pii: rs.3.rs-3673588. [Epub ahead of print]
    Gene signatures derived from transcriptomic-causal networks stratified colorectal cancer patients for effective targeted therapy.
    Akram Yazdani, Heinz-Josef Lenz, Gianluigi Pillonetto, Raul Mendez-Giraldez, Azam Yazdani, Hanna Sanof, Reza Hadi, Esmat Samiei, Alan P Venook, Mark J Ratain, Naim Rashid, Benjamin G Vincent, Xueping Qu, Yujia Wen, Michael Kosorok, William F Symmans, John Paul Y C Shen, Michael S Lee, Scott Kopetz, Andrew B Nixon, Monica M Bertagnolli, Charles M Perou, Federico Innocenti.
      Predictive and prognostic gene signatures derived from interconnectivity among genes can tailor clinical care to patients in cancer treatment. We identified gene interconnectivity as the transcriptomic-causal network by integrating germline genotyping and tumor RNA-seq data from 1,165 patients with metastatic colorectal cancer (CRC). The patients were enrolled in a clinical trial with randomized treatment, either cetuximab or bevacizumab in combination with chemotherapy. We linked the network to overall survival (OS) and detected novel biomarkers by controlling for confounding genes. Our data-driven approach discerned sets of genes, each set collectively stratify patients based on OS. Two signatures under the cetuximab treatment were related to wound healing and macrophages. The signature under the bevacizumab treatment was related to cytotoxicity and we replicated its effect on OS using an external cohort. We also showed that the genes influencing OS within the signatures are downregulated in CRC tumor vs. normal tissue using another external cohort. Furthermore, the corresponding proteins encoded by the genes within the signatures interact each other and are functionally related. In conclusion, this study identified a group of genes that collectively stratified patients based on OS and uncovered promising novel prognostic biomarkers for personalized treatment of CRC using transcriptomic causal networks.
    DOI:  https://doi.org/10.21203/rs.3.rs-3673588/v1
  18. Nat Cell Biol. 2024 Jan 04.
    FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.
    Vera A van der Weijden, Maximilian Stötzel, Dhanur P Iyer, Beatrix Fauler, Elzbieta Gralinska, Mohammed Shahraz, David Meierhofer, Martin Vingron, Steffen Rulands, Theodore Alexandrov, Thorsten Mielke, Aydan Bulut-Karslioglu.
      Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is not known. Here we show that mouse embryos in diapause are sustained by using lipids as primary energy source. In vitro, supplementation of embryos with the metabolite L-carnitine balances lipid consumption, puts the embryos in deeper dormancy and boosts embryo longevity. We identify FOXO1 as an essential regulator of the energy balance in dormant embryos and propose, through meta-analyses of dormant cell signatures, that it may be a common regulator of dormancy across adult tissues. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.
    DOI:  https://doi.org/10.1038/s41556-023-01325-3
  19. Nat Immunol. 2024 Jan 04.
    Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.
    Ronghui Yan, Pinggen Zhang, Shengqi Shen, Yu Zeng, Ting Wang, Zhaolin Chen, Wenhao Ma, Junru Feng, Caixia Suo, Tong Zhang, Haoran Wei, Zetan Jiang, Rui Chen, Shi-Ting Li, Xiuying Zhong, Weidong Jia, Linchong Sun, Chunlei Cang, Huafeng Zhang, Ping Gao.
      Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.
    DOI:  https://doi.org/10.1038/s41590-023-01719-3
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