bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–04–30
nineteen papers selected by
Maria-Virginia Giolito, Free University of Brussels
  1. The 3D Culturing of Organoids from Murine Intestinal Crypts and a Single Stem Cell for Organoid Research.
  2. Effects of hormones on intestinal stem cells.
  3. The Diet as a Modulator of Tumor Microenvironment in Colorectal Cancer Patients.
  4. Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis.
  5. PPARγ agonist pioglitazone enhances colorectal cancer immunotherapy by inducing PD-L1 autophagic degradation.
  6. Young-onset colorectal cancer.
  7. Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.
  8. Immunotherapy with Immune Checkpoint Inhibitors for Advanced Colorectal Cancer: A Promising Individualized Treatment Strategy.
  9. Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability.
  10. Potential effective diagnostic biomarker in patients with primary and metastatic small intestinal neuroendocrine tumors.
  11. A review on emerging targeted therapies for the management of metastatic colorectal cancers.
  12. Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib.
  13. Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us.
  14. Young-onset colorectal cancer.
  15. Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations.
  16. Ptpn2: A Critical Regulator of Paneth Cell Homeostasis.
  17. Differences in DNA damage repair gene mutations between left- and right-sided colorectal cancer.
  18. Glutamate dehydrogenase1 supports HIF-1α stability to promote colorectal tumorigenesis under hypoxia.
  19. Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors.
  1. J Vis Exp. 2023 Apr 07.
    The 3D Culturing of Organoids from Murine Intestinal Crypts and a Single Stem Cell for Organoid Research.
    Yuta Takase, Kazuto Fujishima, Toshio Takahashi.
      At present, organoid culture represents an important tool for in vitro studies of different biological aspects and diseases in different organs. Murine small intestinal crypts can form organoids that mimic the intestinal epithelium when cultured in a 3D extracellular matrix. The organoids are composed of all cell types that fulfill various intestinal homeostatic functions. These include Paneth cells, enteroendocrine cells, enterocytes, goblet cells, and tuft cells. Well-characterized molecules are added into the culture medium to enrich the intestinal stem cells (ISCs) labeled with leucine-rich repeats containing G protein-coupled receptor 5 and are used to drive differentiation down specific lineages; these molecules include epidermal growth factor, Noggin (a bone morphogenetic protein), and R-spondin 1. Additionally, a protocol to generate organoids from a single erythropoietin-producing hepatocellular receptor B2 (EphB2)-positive ISC is also detailed. In this methods article, techniques to isolate small intestinal crypts and a single ISC from tissues and ensure the efficient establishment of organoids are described.
    DOI:  https://doi.org/10.3791/65219
  2. Stem Cell Res Ther. 2023 04 26. 14(1): 105
    Effects of hormones on intestinal stem cells.
    Li Liu, Lilong Zhang, Chunlei Li, Zhendong Qiu, Tianrui Kuang, Zhongkai Wu, Wenhong Deng.
      The maintenance of intestinal renewal and repair mainly depends on intestinal stem cells (ISCs), which can also contribute to the growth of intestinal tumours. Hormones, which are vital signalling agents in the body, have various effects on the growth and replacement of intestinal stem cells. This review summarises recent progress in the identification of hormones associated with intestinal stem cells. Several hormones, including thyroid hormone, glucagon-like peptide-2, androgens, insulin, leptin, growth hormone, corticotropin-releasing hormone and progastrin, promote the development of intestinal stem cells. However, somatostatin and melatonin are two hormones that prevent the proliferation of intestinal stem cells. Therefore, new therapeutic targets for the diagnosis and treatment of intestinal illnesses can be identified by examining the impact of hormones on intestinal stem cells.
    Keywords:  Hormones; Intestinal stem cells; Stem cell; Therapy
    DOI:  https://doi.org/10.1186/s13287-023-03336-1
  3. Int J Mol Sci. 2023 Apr 15. pii: 7317. [Epub ahead of print]24(8):
    The Diet as a Modulator of Tumor Microenvironment in Colorectal Cancer Patients.
    Manuel Collado, Marién Castillo, Gemma Julia Muñoz de Mier, Carolina de la Pinta, Cristina Peña.
      Colorectal cancer (CRC) is one of the most common cancers in Western countries and remains the second most common cause of cancer death worldwide. Many studies show the importance of diet and lifestyle in the incidence of CRC, as well as in CRC prevention. However, this review summarizes those studies that analyze the impact of nutrition on tumor microenvironment modulation and cancer progression. We review the available information about the effects of specific nutrients on cancer cell progression and on the different cells within the tumor microenvironment. Diet and nutritional status in the clinical management of colorectal cancer patients are also analyzed. Finally, future perspectives and challenges are discussed, with a view to improving CRC treatments by employing nutritional approaches. These promise great benefits and will eventually improve CRC patients' survival.
    Keywords:  colorectal cancer; diet; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms24087317
  4. Mol Cancer Res. 2023 Apr 25. pii: MCR-22-1000. [Epub ahead of print]
    Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis.
    Jiahn Choi, Xusheng Zhang, Wenge Li, Michele Houston, Karina Peregrina, Robert Dubin, Kenny Ye, Leonard Augenlicht.
      NWD1, a purified diet establishing mouse exposure to key nutrients recapitulating levels that increase human risk for intestinal cancer, reproducibly causes mouse sporadic intestinal and colonic tumors reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 stem cell and lineage reprogramming was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly, reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lgr5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Implications: Although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-1000
  5. Eur J Pharmacol. 2023 Apr 25. pii: S0014-2999(23)00260-1. [Epub ahead of print] 175749
    PPARγ agonist pioglitazone enhances colorectal cancer immunotherapy by inducing PD-L1 autophagic degradation.
    Xiao Jia, Jin Qian, Huiqing Chen, Qian Liu, Shakeel Hussain, Jianhua Jin, Juanjuan Shi, Yongzhong Hou.
      Blockade of PD-1/PD-L1 immune checkpoint could be an effective antitumor strategy for multiple types of cancer, but it is low response rate for colorectal cancer patients with unclear mechanism. Here we found that PPARγ agonist pioglitazone could reduce PD-L1 protein levels without effect on its gene expression. Further analysis showed that pioglitazone induced PD-L1 autophagic degradation in a PPARγ-dependent manner. Pioglitazone promoted PD-L1 translocation to lysosome by immunofluorescence analysis, which was associated with the increased binding of PPARγ to PD-L1. Moreover the combined pioglitazone with PD-1 antibody enhanced colorectal tumor immunotherapy, which was involved in reduced PD-L1 levels and increased CD8+ T cells. These findings suggest that PPARγ agonist could induce PD-L1 autophagic degradation resulting in increased colorectal tumor immunotherapy.
    Keywords:  Autophagic degradation; Colorectal tumor immunotherapy; PD-L1; Pioglitazone
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175749
  6. Nat Rev Dis Primers. 2023 Apr 27. 9(1): 22
    Young-onset colorectal cancer.
      
    DOI:  https://doi.org/10.1038/s41572-023-00436-3
  7. iScience. 2023 Apr 21. 26(4): 106478
    Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.
    Hiroaki Itakura, Tsuyoshi Hata, Daisuke Okuzaki, Koki Takeda, Kenji Iso, Yamin Qian, Yoshihiro Morimoto, Tomohiro Adachi, Haruka Hirose, Yuhki Yokoyama, Takayuki Ogino, Norikatsu Miyoshi, Hidekazu Takahashi, Mamoru Uemura, Tsunekazu Mizushima, Takao Hinoi, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Hirofumi Yamamoto.
      Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate-treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.
    Keywords:  Cancer; Molecular biology; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2023.106478
  8. Front Biosci (Landmark Ed). 2023 Apr 06. 28(4): 69
    Immunotherapy with Immune Checkpoint Inhibitors for Advanced Colorectal Cancer: A Promising Individualized Treatment Strategy.
    Ying Yang, Wen-Jian Meng, Zi-Qiang Wang.
      Colorectal cancer (CRC) is one of the high incident and lethal malignant tumors, and most of the patients are diagnosed at an advanced stage. The treatment of CRC mainly includes surgery, chemotherapy, radiotherapy and molecular targeted therapy. Despite these approaches have increased overall survival (OS) of CRC patients, the prognosis of advanced CRC remains poor. In recent years, remarkable breakthroughs have been made in tumor immunotherapy, especially immune checkpoint inhibitors (ICIs) therapy, bringing long-term survival benefits to tumor patients. With the increasing wealth of clinical data, ICIs have achieved significant efficacy in the treatment of high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) advanced CRC, but the therapeutic effects of ICIs on microsatellite stable (MSS) advanced CRC patients is currently unsatisfactory. As increasing numbers of large clinical trials are performed globally, patients treated with ICIs therapy also have immunotherapy-related adverse events and treatment resistance. Therefore, a large number of clinical trials are still needed to evaluate the therapeutic effect and safety of ICIs therapy in advanced CRC. This article will focus on the current research status of ICIs in advanced CRC and discuss the current predicament of ICIs treatment.
    Keywords:  colorectal cancer; deficient mismatch repair; immune checkpoint inhibitors; immunotherapy; microsatellite instability
    DOI:  https://doi.org/10.31083/j.fbl2804069
  9. BMC Med. 2023 Apr 27. 21(1): 161
    Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability.
    Tao Wu, Xuan Zhang, Xinxing Liu, Xinyi Cai, Tao Shen, Dingguo Pan, Rui Liang, Rong Ding, Ruixi Hu, Jianhua Dong, Furong Li, Jinsha Li, Lin Xie, Chunlong Wang, Shilei Geng, Zhaoyu Yang, Lu Xing, YunFeng Li.
       BACKGROUND: The objective response rate of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients with first-line anti-programmed cell death protein-1 (PD-1) monotherapy is only 40-45%. Single-cell RNA sequencing (scRNA-seq) enables unbiased analysis of the full variety of cells comprising the tumor microenvironment. Thus, we used scRNA-seq to assess differences among microenvironment components between therapy-resistant and therapy-sensitive groups in MSI-H/mismatch repair-deficient (dMMR) mCRC. Resistance-related cell types and genes identified by this analysis were subsequently verified in clinical samples and mouse models to further reveal the molecular mechanism of anti-PD-1 resistance in MSI-H or dMMR mCRC.
    METHODS: The response of primary and metastatic lesions to first-line anti-PD-1 monotherapy was evaluated by radiology. Cells from primary lesions of patients with MSI-H/dMMR mCRC were analyzed using scRNA-seq. To identify the marker genes in each cluster, distinct cell clusters were identified and subjected to subcluster analysis. Then, a protein‒protein interaction network was constructed to identify key genes. Immunohistochemistry and immunofluorescence were applied to verify key genes and cell marker molecules in clinical samples. Immunohistochemistry, quantitative real-time PCR, and western blotting were performed to examine the expression of IL-1β and MMP9. Moreover, quantitative analysis and sorting of myeloid-derived suppressor cells (MDSCs) and CD8+ T cells were performed using flow cytometry.
    RESULTS: Tumor responses in 23 patients with MSI-H/dMMR mCRC were evaluated by radiology. The objective response rate was 43.48%, and the disease control rate was 69.57%. ScRNA-seq analysis showed that, compared with the treatment-resistant group, the treatment-sensitive group accumulated more CD8+ T cells. Experiments with both clinical samples and mice indicated that infiltration of IL-1β-driven MDSCs and inactivation of CD8+ T cells contribute to anti-PD-1 resistance in MSI-H/dMMR CRC.
    CONCLUSIONS: CD8+ T cells and IL-1β were identified as the cell type and gene, respectively, with the highest correlation with anti-PD-1 resistance. Infiltration of IL-1β-driven MDSCs was a significant factor in anti-PD-1 resistance in CRC. IL-1β antagonists are expected to be developed as a new treatment for anti-PD-1 inhibitor resistance.
    Keywords:  Deficient mismatch repair (dMMR); Interleukin-1 beta (IL-1β); Metastatic colorectal cancer (mCRC); Myeloid-derived suppressor cells (MDSCs); Programmed cell death protein-1(PD-1); microsatellite instability-high (MSI-H)
    DOI:  https://doi.org/10.1186/s12916-023-02866-y
  10. Front Genet. 2023 ;14 1110396
    Potential effective diagnostic biomarker in patients with primary and metastatic small intestinal neuroendocrine tumors.
    Jianxian Chen, Yiliang Meng, Xiaojuan Huang, Xuegan Liao, Xiaochun Tang, Yuanchao Xu, Jie Li.
      Background: Small intestinal neuroendocrine tumors (SI-NETs) are the most common malignant tumors of the small intestine, with many patients presenting with metastases and their incidence increasing. We aimed to find effective diagnostic biomarkers for patients with primary and metastatic SI-NETs that could be applied for clinical diagnosis. Methods: We downloaded GSE65286 (training set) and GSE98894 (test set) from the GEO database and performed differential gene expression analysis to obtain differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs). The functions and pathways involved in these genes were further explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In addition, a global regulatory network involving dysregulated genes in SI-NETs was constructed based on RNAInter and TRRUST v2 databases, and the diagnostic power of hub genes was identified by receiver operating characteristic curve (ROC). Results: A total of 2,969 DEGs and DElncRNAs were obtained in the training set. Enrichment analysis revealed that biological processes (BPs) and KEGG pathways were mainly associated with cancer. Based on gene set enrichment analysis (GSEA), we obtained five BPs (cytokinesis, iron ion homeostasis, mucopolysaccharide metabolic process, platelet degranulation and triglyceride metabolic process) and one KEGG pathway (ppar signaling pathway). In addition, the core set of dysregulated genes obtained included MYL9, ITGV8, FGF2, FZD7, and FLNC. The hub genes were upregulated in patients with primary SI-NETs compared to patients with metastatic SI-NETs, which is consistent with the training set. Significantly, the results of ROC analysis showed that the diagnostic power of the hub genes was strong in both the training and test sets. Conclusion: In summary, we constructed a global regulatory network in SI-NETs. In addition, we obtained the hub genes including MYL9, ITGV8, FGF2, FZD7, and FLNC, which may be useful for the diagnosis of patients with primary and metastatic SI-NETs.
    Keywords:  hub genes; intestinal neuroendocrine tumor; lncRNA; metastatic small intestinal neuroendocrine rumors; primary small intestinal neuroendocrine tumor
    DOI:  https://doi.org/10.3389/fgene.2023.1110396
  11. Med Oncol. 2023 Apr 25. 40(6): 159
    A review on emerging targeted therapies for the management of metastatic colorectal cancers.
    Rohitas Deshmukh, Mahendra Prajapati, Ranjit K Harwansh.
      Colorectal cancers are among the most commonly found cancers over the world. In spite of the recent advancements in diagnosis and prognosis, the management of this metastatic condition remains a challenge. The utility of monoclonal antibodies in the healing of patients with colorectal cancer has opened a new chapter in the quest for newer therapies. The resistance to the standard treatment regimen made it mandatory to search for newer targets. Mutagenic alterations in the gene engaged in cellular differentiation and growth pathway have been the reason for resistance to treatment. The newer therapies target the various proteins and receptors involved in the signal transduction and down streaming pathways leading to cell proliferation. This review presents an insight into the newer targeted therapies for colorectal cancer involving tyrosine kinase blockers, epidermal growth factor receptors, vascular endothelial growth factor, immune checkpoint therapy, and BRAF inhibitors.
    Keywords:  Colorectal cancer; EGFR; KRAS; Median overall survival; Mutation; VEGF
    DOI:  https://doi.org/10.1007/s12032-023-02020-x
  12. Biology (Basel). 2023 Apr 17. pii: 608. [Epub ahead of print]12(4):
    Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib.
    Iris Car, Antje Dittmann, Marko Klobučar, Petra Grbčić, Sandra Kraljević Pavelić, Mirela Sedić.
      Patients with metastatic colorectal cancer (mCRC) carrying BRAFV600E mutation have worse response to chemotherapy and poor prognosis. The BRAFV600E inhibitor vemurafenib has shown modest efficacy as monotherapy in BRAF-mutated mCRC due to the development of resistance. The aim of this study was to conduct a comparative proteomics profiling of the secretome from vemurafenib-sensitive vs. -resistant colon cancer cells harboring BRAFV600E mutation in order to identify specific secretory features potentially associated with changes in the resistant cells' phenotype. Towards this aim, we employed two complementary proteomics approaches including two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry and label-free quantitative LC-MS/MS analysis. Obtained results pointed to aberrant regulation of DNA replication and endoplasmic reticulum stress as the major secretome features associated with chemoresistant phenotype. Accordingly, two proteins implicated in these processes including RPA1 and HSPA5/GRP78 were discussed in more details in the context of biological networks and their importance as potential secretome targets for further functional and clinical evaluation. Expression patterns of RPA1 and HSPA5/GRP78 in tumor tissues from colon cancer patients were also found in additional in silico analyses to be associated with BRAFV600E mutation status, which opens the possibility to extrapolate our findings and their clinical implication to other solid tumors harboring BRAFV600E mutation, such as melanoma.
    Keywords:  BRAF inhibition; BRAFV600E; DNA replication; ER stress; HSPA5/GRP78; RPA1; chemoresistance; colon cancer; secretome; vemurafenib
    DOI:  https://doi.org/10.3390/biology12040608
  13. Int J Mol Sci. 2023 Apr 13. pii: 7233. [Epub ahead of print]24(8):
    Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us.
    Santosh Kumar, Michael Y Sherman.
      Irinotecan (SN-38) is a potent and broad-spectrum anticancer drug that targets DNA topoisomerase I (Top1). It exerts its cytotoxic effects by binding to the Top1-DNA complex and preventing the re-ligation of the DNA strand, leading to the formation of lethal DNA breaks. Following the initial response to irinotecan, secondary resistance is acquired relatively rapidly, compromising its efficacy. There are several mechanisms contributing to the resistance, which affect the irinotecan metabolism or the target protein. In addition, we have demonstrated a major resistance mechanism associated with the elimination of hundreds of thousands of Top1 binding sites on DNA that can arise from the repair of prior Top1-dependent DNA cleavages. Here, we outline the major mechanisms of irinotecan resistance and highlight recent advancements in the field. We discuss the impact of resistance mechanisms on clinical outcomes and the potential strategies to overcome resistance to irinotecan. The elucidation of the underlying mechanisms of irinotecan resistance can provide valuable insights for the development of effective therapeutic strategies.
    Keywords:  DNA damage response; DNA repair; chemotherapy; dose escalation; drug resistance; irinotecan; topoisomerase I
    DOI:  https://doi.org/10.3390/ijms24087233
  14. Nat Rev Dis Primers. 2023 Apr 27. 9(1): 21
    Young-onset colorectal cancer.
    Manon C W Spaander, Ann G Zauber, Sapna Syngal, Martin J Blaser, Joseph J Sung, Y Nancy You, Ernst J Kuipers.
      In the past decades the incidence of colorectal cancer (CRC) in people under the age of 50 years has increased, which is referred to as early-onset CRC or young-onset CRC (YO-CRC). YO-CRC is expected to account for 11% of colon cancers and 23% of rectal cancers by 2030. This trend is observed in different parts of the world and in both men and women. In 20% of patients with YO-CRC, a hereditary cancer syndrome is found as the underlying cause; however, in the majority of patients no genetic predisposition is present. Beginning in the 1950s, major changes in lifestyle such as antibiotic use, low physical activity and obesity have affected the gut microbiome and may be an important factor in YO-CRC development. Owing to a lack of screening, patients with YO-CRC are often diagnosed with advanced-stage disease. Long-term treatment-related complications should be taken into account in these younger patients, making the more traditional sequential approaches of drug therapy not always the most appropriate option. To better understand the underlying mechanism and define relationships between environmental factors and YO-CRC development, long-term prospective studies are needed with lifestyle data collected from childhood.
    DOI:  https://doi.org/10.1038/s41572-023-00432-7
  15. Redox Biol. 2023 Apr 14. pii: S2213-2317(23)00100-3. [Epub ahead of print]62 102699
    Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations.
    Hong Yan, Ronan Talty, Abhishek Jain, Yuping Cai, Jie Zheng, Xinyi Shen, Engjel Muca, Philip B Paty, Marcus W Bosenberg, Sajid A Khan, Caroline H Johnson.
      Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that only in male patients, tumors with KRAS mutations had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO)), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppress ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Additionally, low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.
    Keywords:  Colorectal cancer; Ferroptosis; KRAS; Metabolomics; Sex differences
    DOI:  https://doi.org/10.1016/j.redox.2023.102699
  16. Cell Mol Gastroenterol Hepatol. 2023 Apr 22. pii: S2352-345X(23)00050-4. [Epub ahead of print]
    Ptpn2: A Critical Regulator of Paneth Cell Homeostasis.
    Arianne L Theiss.
      
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.03.010
  17. Cancer Med. 2023 Apr 25.
    Differences in DNA damage repair gene mutations between left- and right-sided colorectal cancer.
    Wei Huang, Wenliang Li, Ning Xu, Hui Li, Zihan Zhang, Xiaolong Zhang, Tingting He, Jicheng Yao, Mian Xu, Qingqing He, Lijie Guo, Sen Zhang.
       BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Studies have shown that the DNA damage response (DDR) mutation is strongly associated with microsatellite instability (MSI) status and is an indication for patients with CRCs receiving immune checkpoint inhibitor (ICI) treatment. However, DDR mutation in microsatellite stable (MSS) CRC remains unclear.
    METHODS: In this study, Fisher's exact test, Student'st-test, Wilcoxon rank-sum test and Cox proportional hazards regression model were performed, and a p value of < 0.05 was considered statistically significant.
    RESULTS: The most common gene alterations were APC (77%), TP53 (73%), KRAS (48%), and PIK3CA (25%). The mutationfrequency of APC and TP53 in left-sided CRC was significantly higher than that for right-sided CRC, while the mutation frequency of PIK3CA, ACVR2A, FAT4, and RNF43 in right-sided CRC was significantly higher than that for left-sided CRC. DDR mutations occurred in100% of MSI CRCs and in 83.77% of MSS CRCs, with the most frequently mutated DDR genes being ARID1A (7.5%), ATM (5.7%,) and BRCA2 (2.6%). When right- and left-sided CRCs were compared, no significant difference was observed for DDR genes and pathways. A survival analysis indicated that the DDR mutation was not associated with overall survival (OS) in MSS CRCs, while left-sided patients with homologous recombination repair (HRR) pathway mutations had a significantly prolonged OS compared with right-sided CRCs.
    CONCLUSIONS: Here, we found that stage and grade were statistically significant independent prognostic factors in the left-sided CRC and the right-sided CRC, recommending treatment for these patients stratified by stage. For the future, utilizing DDR gene defects for expanding treatment options and improving prognosis is an issue worth exploring.
    Keywords:  DDR mutations; MSS CRC; genomic landscape; prognosis
    DOI:  https://doi.org/10.1002/cam4.5716
  18. EMBO J. 2023 Apr 24. e112675
    Glutamate dehydrogenase1 supports HIF-1α stability to promote colorectal tumorigenesis under hypoxia.
    Kunhua Hu, Yufeng Ding, Hongwen Zhu, Xiaoqian Jing, Weiling He, Hua Yu, Xiongjun Wang.
      Tumor cells surviving hypoxic stress acquire the ability to drive cancer progression. To explore the contribution of dehydrogenases to the low oxygen concentration response, we used siRNAs targeting 163 dehydrogenase-coding genes and discovered that glutamate dehydrogenase 1 (GDH1) plays a critical role in regulating colorectal cancer (CRC) cell survival under hypoxia. We observed that GDH1 deficiency had an inhibitory effect on CRC occurrence and impaired hypoxia-inducible factor 1-alpha (HIF-1α) stability even under hypoxia. Mechanistically, hypoxia triggered p300 recruitment to GDH1, promoting its acetylation at K503 and K527. GDH1 acetylation at K527 induced the formation of a GDH1 complex with EGLN1/HIF-1α; in contrast, GDH1 acetylation at K503 reinforced its affinity for α-ketoglutarate (αKG), and glutamate production. In line with this view, αKG is a product of GDH1 under normoxia, but hypoxia stimulation reversed GDH1 enzyme activity and αKG consumption by the EGLN1/HIF-1α complex, increasing HIF-1α stability and promoting CRC progression. Clinically, hypoxia-modulated GDH1 AcK503/527 can be used as a biomarker of CRC progression and is a potential target for CRC treatment.
    Keywords:  GDH1; HIF1α; acetylation; colorectal cancer; α-ketoglutarate
    DOI:  https://doi.org/10.15252/embj.2022112675
  19. Eur J Cancer. 2023 Mar 31. pii: S0959-8049(23)00165-X. [Epub ahead of print]187 15-24
    Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors.
    Paolo Manca, Francesca Corti, Rossana Intini, Giacomo Mazzoli, Rosalba Miceli, Marco Maria Germani, Francesca Bergamo, Margherita Ambrosini, Eleonora Cristarella, Riccardo Cerantola, Chiara Boccaccio, Gianmarco Ricagno, Filippo Ghelardi, Giovanni Randon, Giuseppe Leoncini, Massimo Milione, Matteo Fassan, Chiara Cremolini, Sara Lonardi, Filippo Pietrantonio.
       BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes.
    PATIENTS AND METHODS: We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen.
    RESULTS: We included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8-251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio [aHR] = 4.26, 95% confidence interval [CI]:1.85-9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76-14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949).
    CONCLUSION: Patients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination.
    Keywords:  Immune checkpoint inhibitors; Metastatic colorectal cancer; Microsatellite instability; Mismatch repair deficiency; Tumour mutational burden
    DOI:  https://doi.org/10.1016/j.ejca.2023.03.029
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