bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–08–25
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. The lipid-metabolism enzyme ECI2 reduces neutrophil extracellular traps formation for colorectal cancer suppression.
  2. Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
  3. Spatial transcriptomic revealed intratumor heterogeneity and cancer stem cell enrichment in colorectal cancer metastasis.
  4. Short-term post-fast refeeding enhances intestinal stemness via polyamines.
  5. Impact of primary tumor sidedness and sex on prognosis and anti-epidermal growth factor receptor antibody efficacy in BRAF-mutant metastatic colorectal cancer: a pooled analysis of AIO studies FIRE-1, CIOX, FIRE-3, XELAVIRI, and VOLFI.
  6. Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort.
  7. Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer.
  8. Cancer tissue of origin constrains the growth and metabolism of metastases.
  9. Endothelial cell heterogeneity in colorectal cancer: tip cells drive angiogenesis.
  10. Dynamic regulation of tissue fluidity controls skin repair during wound healing.
  11. Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight.
  12. tsRNA-GlyGCC promotes colorectal cancer progression and 5-FU resistance by regulating SPIB.
  13. Meta-analysis revisiting the influence of UGT1A1*28 and UGT1A1*6 on irinotecan safety in colorectal cancer patients.
  1. Nat Commun. 2024 Aug 21. 15(1): 7184
    The lipid-metabolism enzyme ECI2 reduces neutrophil extracellular traps formation for colorectal cancer suppression.
    Lixia Chen, Peiling Dai, Lei Liu, Yujia Chen, Yanxia Lu, Lin Zheng, Haowei Wang, Qinzi Yuan, Xuenong Li.
      Abnormalities in ether lipid metabolism as well as the formation of neutrophil extracellular traps have recently been recognized as detrimental factors affecting tumorigenesis and progression. However, the role of abnormal ether lipid metabolism in colorectal cancer (CRC) evolution has not been reported. Here we show that the lipid metabolism-related gene enoyl-CoA δ-isomerase 2 (ECI2) plays a tumor-suppressor role in CRC and is negatively associated with poor prognosis in CRC patients. We mechanistically demonstrate that ECI2 reduces ether lipid-mediated Interleukin 8 (IL-8) expression leading to decreased neutrophil recruitment and neutrophil extracellular traps formation for colorectal cancer suppression. In particular, ECI2 inhibits ether lipid production in CRC cells by inhibiting the peroxisomal localization of alkylglycerone phosphate synthase (AGPS), the rate-limiting enzyme for ether lipid synthesis. These findings not only deepen our understanding of the role of metabolic reprogramming and neutrophil interactions in the progression of CRC, but also provide ideas for identifying potential diagnostic markers and therapeutic targets for CRC.
    DOI:  https://doi.org/10.1038/s41467-024-51489-1
  2. Nature. 2024 Aug 21.
    Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
    Katherine S Stewart, Merve Deniz Abdusselamoglu, Matthew T Tierney, Anita Gola, Yun Ha Hur, Kevin A U Gonzales, Shaopeng Yuan, Alain R Bonny, Yihao Yang, Nicole R Infarinato, Christopher J Cowley, John M Levorse, Hilda Amalia Pasolli, Sourav Ghosh, Carla V Rothlin, Elaine Fuchs.
      Billions of cells are eliminated daily from our bodies1-4. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses1-4. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARγ-RXRα, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche.
    DOI:  https://doi.org/10.1038/s41586-024-07855-6
  3. Cancer Lett. 2024 Aug 17. pii: S0304-3835(24)00576-7. [Epub ahead of print] 217181
    Spatial transcriptomic revealed intratumor heterogeneity and cancer stem cell enrichment in colorectal cancer metastasis.
    Leqi Zhou, Rongbo Wen, Chenguang Bai, Zhixuan Li, Kuo Zheng, Yue Yu, Tianshuai Zhang, Hang Jia, Zhiyin Peng, Xiaoming Zhu, Zheng Lou, Liqiang Hao, Guanyu Yu, Fu Yang, Wei Zhang.
      Metastasis is the main cause of mortality in colorectal cancer (CRC) patients. Exploring the mechanisms of metastasis is of great importance in both clinical and fundamental CRC research. CRC is a highly heterogeneous disease with variable therapeutic outcomes of treatment. In this study, we applied spatial transcriptomics (ST) to generate a tissue-wide transcriptome from two primary colorectal cancer tissues and their matched liver metastatic tissues. Spatial RNA information showed intratumoral heterogeneity (ITH) of both primary and metastatic tissues. The comparison of gene expressions across tissues revealed an apparent enrichment of cancer stem cells (CSCs) in metastatic tissues and identified FOXD1 as a novel metastatic CSC marker. Trajectory and pseudo-time analyses revealed distinct evolutionary trajectories and a dedifferentiation-differentiation process during metastasis. CellphoneDB analysis suggested a dominant interaction of CD74-MIF with tumor cells in metastatic tissues. Further analysis confirmed FOXD1 as a maker of CSCs and the predictor of patient survival, especially in metastatic diseases. Our study found ITH of primary and metastatic tissues and provides novel insights into the cellular mechanisms underlying liver metastasis of CRC and foundations for therapeutic strategies for CRC metastasis.
    Keywords:  cancer stem cell; colorectal cancer; intratumoral heterogeneity; liver metastasis; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.canlet.2024.217181
  4. Nature. 2024 Aug 21.
    Short-term post-fast refeeding enhances intestinal stemness via polyamines.
    Shinya Imada, Saleh Khawaled, Heaji Shin, Sven W Meckelmann, Charles A Whittaker, Renan Oliveira Corrêa, Chiara Alquati, Yixin Lu, Guodong Tie, Dikshant Pradhan, Gizem Calibasi-Kocal, Luiza Martins Nascentes Melo, Gabriele Allies, Jonas Rösler, Pia Wittenhofer, Jonathan Krystkiewicz, Oliver J Schmitz, Jatin Roper, Marco Aurelio Ramirez Vinolo, Luigi Ricciardiello, Evan C Lien, Matthew G Vander Heiden, Ramesh A Shivdasani, Chia-Wei Cheng, Alpaslan Tasdogan, Ömer H Yilmaz.
      For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans1-6. However, how fasting and post-fast refeeding affect adult stem cells and tumour formation has yet to be explored in depth. Here we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation; post-fast refeeding augments the regenerative capacity of Lgr5+ ISCs, and loss of the tumour suppressor gene Apc in post-fast-refed ISCs leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum-fed states, demonstrating that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust mTORC1 induction in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production or protein synthesis abrogates the regenerative or tumorigenic effects of post-fast refeeding. Given our findings, fast-refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity.
    DOI:  https://doi.org/10.1038/s41586-024-07840-z
  5. ESMO Open. 2024 Aug 21. pii: S2059-7029(24)01446-7. [Epub ahead of print]9(9): 103677
    Impact of primary tumor sidedness and sex on prognosis and anti-epidermal growth factor receptor antibody efficacy in BRAF-mutant metastatic colorectal cancer: a pooled analysis of AIO studies FIRE-1, CIOX, FIRE-3, XELAVIRI, and VOLFI.
    A H S Alig, D P Modest, S Stintzing, K Heinrich, M Geissler, L Fischer von Weikersthal, T Decker, U Vehling-Kaiser, S Held, N Moosmann, A Stahler, A Tannapfel, C Giessen-Jung, A Jung, L Weiss, V Heinemann.
       BACKGROUND: Primary tumor (PT) sidedness is an established prognostic marker in metastatic colorectal cancer (mCRC) and has a predictive impact on the efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibody [monoclonal antibody (mAb)] in patients with RAS wild-type mCRC. This investigation focuses on patients with BRAFV600E-mutated (BRAFmt) mCRC and examines the efficacy of anti-EGFR mAbs in relation to primary tumor sidedness (PTS).
    PATIENT AND METHODS: This pooled analysis was carried out using individual patient data from five randomized studies in the first-line setting of mCRC. The population of interest was limited to patients with BRAFmt mCRC and known PTS. For analysis, treatment was stratified into two groups: those treated with anti-EGFR mAbs and those without. Dichotomous variables, such as overall response rate and objective response rate (ORR), were compared using chi-square or Fisher's exact test. Time-to-event endpoints [progression-free survival (PFS) and overall survival (OS)] were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. An interaction test was carried out via Cox regression.
    RESULTS: A total of 102 patients with BRAFmt mCRC were identified. The type of targeted therapy (anti-EGFR-based versus non-anti-EGFR) did not significantly impact the outcome. However, in patients with left-sided primary tumors, anti-EGFR mAb-based treatment, compared with non-anti-EGFR, was associated with a higher ORR (58% versus 34%; P < 0.01), trended toward improved PFS [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.34-1.13; P = 0.12], and demonstrated prolonged OS (HR 0.38; 95% CI 0.20-0.72; P < 0.01). In patients with right-sided primary tumors, anti-EGFR-based therapy had no effect on ORR (33% versus 36%; P > 0.99), induced inferior PFS (HR 1.97; 95% CI 1.12-3.47; P = 0.02), and trended toward a worse OS (HR 1.76; 95% CI 0.99-3.13; P = 0.05).
    CONCLUSION: This analysis suggests that PTS has predictive value for the efficacy of anti-EGFR mAb in the first-line treatment of BRAFmt mCRC.
    Keywords:  BRAF mutation; EGFR antibody; metastatic colorectal cancer; primary tumor location; primary tumor sidedness
    DOI:  https://doi.org/10.1016/j.esmoop.2024.103677
  6. Transl Res. 2024 Aug 16. pii: S1931-5244(24)00147-6. [Epub ahead of print]
    Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort.
    Marjolein F Lansbergen, Mark P G Dings, Paul Manoukian, Arantza Farina, Cynthia Waasdorp, Gerrit K J Hooijer, Joanne Verheij, Jan Koster, Danny A Zwijnenburg, Johanna W Wilmink, Jan Paul Medema, Frederike Dijk, Hanneke W M van Laarhoven, Maarten F Bijlsma.
      Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6low patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.
    Keywords:  carcinoma, pancreatic ductal; drug resistance, neoplasm; folfirinox; gene expression profiling; immunohistochemistry
    DOI:  https://doi.org/10.1016/j.trsl.2024.08.002
  7. Cancer Sci. 2024 Aug 22.
    Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer.
    Yuya Yoshida, Masanobu Takahashi, Sakura Taniguchi, Ryunosuke Numakura, Keigo Komine, Chikashi Ishioka.
      Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.
    Keywords:  BRAF inhibitor; MEK inhibitor; colorectal cancer; retinoid; tretinoin
    DOI:  https://doi.org/10.1111/cas.16280
  8. Nat Metab. 2024 Aug 19.
    Cancer tissue of origin constrains the growth and metabolism of metastases.
    Sharanya Sivanand, Yetis Gultekin, Peter S Winter, Sidney Y Vermeulen, Konstantine M Tchourine, Keene L Abbott, Laura V Danai, Florian Gourgue, Brian T Do, Kayla Crowder, Tenzin Kunchok, Allison N Lau, Alicia M Darnell, Alexandria Jefferson, Satoru Morita, Dan G Duda, Andrew J Aguirre, Brian M Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J Irvine, Omer H Yilmaz, Caroline A Lewis, Dennis Vitkup, Alex K Shalek, Matthew G Vander Heiden.
      Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize.
    DOI:  https://doi.org/10.1038/s42255-024-01105-9
  9. Cell Mol Life Sci. 2024 Aug 22. 81(1): 365
    Endothelial cell heterogeneity in colorectal cancer: tip cells drive angiogenesis.
    Zhenyu Xie, Liaoran Niu, Kunli Du, Ling Chen, Gaozan Zheng, Songchen Dai, Hanjun Dan, Lili Duan, Xinyu Dou, Fan Feng, Jian Zhang, Jianyong Zheng.
      This study aims to uncover the heterogeneity of endothelial cells (ECs) in colorectal cancer (CRC) and their crucial role in angiogenesis, with a special focus on tip cells. Using single-cell RNA sequencing to profile ECs, our data suggests that CRC ECs predominantly exhibit enhanced angiogenesis and decreased antigen presentation, a shift in phenotype largely steered by tip cells. We also observed that an increase in the density and proportion of tip cells correlates with CRC occurrence, progression, and poorer patient prognosis. Furthermore, we identified endothelial cell-specific molecule 1 (ESM1), specifically expressed in tip cells, sustains a VEGFA-KDR-ESM1 positive feedback loop, promoting angiogenesis and CRC proliferation and migration. We also found the enrichment of KDR in tip cells and spotlight a unique long-tail effect in VEGFA expression: while VEGFA is primarily expressed by epithelial cells, the highest level of VEGFA expression is found in individual myeloid cells. Moreover, we observed that effective PD-1 blockade immunotherapy significantly reduced tip cells, disrupting the VEGFA-KDR-ESM1 positive feedback loop in the process. Our investigation into the heterogeneity of ECs in CRC at a single-cell level offers important insights that may contribute to the development of more effective immunotherapies targeting tip cells in CRC.
    Keywords:  Angiogenesis; Colorectal cancer; ESM1; Endothelial cell; Single-cell RNA sequencing; Tip cell
    DOI:  https://doi.org/10.1007/s00018-024-05411-z
  10. Cell. 2024 Aug 11. pii: S0092-8674(24)00825-0. [Epub ahead of print]
    Dynamic regulation of tissue fluidity controls skin repair during wound healing.
    Rahul M Sarate, Joel Hochstetter, Manon Valet, Adrien Hallou, Yura Song, Nordin Bansaccal, Melanie Ligare, Mariaceleste Aragona, Dan Engelman, Anaïs Bauduin, Otger Campàs, Benjamin D Simons, Cedric Blanpain.
      During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.
    Keywords:  AP1 transcription factor; Voronoi model; intravital; lineage ablation; regenerative state; skin; stem cells; tissue fluidity; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cell.2024.07.031
  11. Cancer Cell Int. 2024 Aug 22. 24(1): 295
    Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight.
    Zhongshu Lin, Guanxiang Hua, Xiaojuan Hu.
      Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.
    DOI:  https://doi.org/10.1186/s12935-024-03481-4
  12. J Exp Clin Cancer Res. 2024 Aug 17. 43(1): 230
    tsRNA-GlyGCC promotes colorectal cancer progression and 5-FU resistance by regulating SPIB.
    Rong Xu, Ashuai Du, Xinpei Deng, Wei Du, Kaiying Zhang, Jianbo Li, Yingxue Lu, Xiaoli Wei, Qinglong Yang, Hailin Tang.
       BACKGROUND: tRNA-derived small RNAs (tsRNAs) are newly discovered non-coding RNA, which are generated from tRNAs and are reported to participate in several biological processes in diseases, especially cancer; however, the mechanism of tsRNA involvement in colorectal cancer (CRC) and 5-fluorouracil (5-FU) is still unclear.
    METHODS: RNA sequencing was performed to identify differential expression of tsRNAs in CRC tissues. CCK8, colony formation, transwell assays, and tumor sphere assays were used to investigate the role of tsRNA-GlyGCC in 5-FU resistance in CRC. TargetScan and miRanda were used to identify the target genes of tsRNA-GlyGCC. Biotin pull-down, RNA pull-down, luciferase assay, ChIP, and western blotting were used to explore the underlying molecular mechanisms of action of tsRNA-GlyGCC. The MeRIP assay was used to investigate the N(7)-methylguanosine RNA modification of tsRNA-GlyGCC.
    RESULTS: In this study, we uncovered the feature of tsRNAs in human CRC tissues and confirmed a specific 5' half tRNA, 5'tiRNA-Gly-GCC (tsRNA-GlyGCC), which is upregulated in CRC tissues and modulated by METTL1-mediated N(7)-methylguanosine tRNA modification. In vitro and in vivo experiments revealed the oncogenic role of tsRNA-GlyGCC in 5-FU drug resistance in CRC. Remarkably, our results showed that tsRNA-GlyGCC modulated the JAK1/STAT6 signaling pathway by targeting SPIB. Poly (β-amino esters) were synthesized to assist the delivery of 5-FU and tsRNA-GlyGCC inhibitor, which effectively inhibited tumor growth and enhanced CRC sensitive to 5-FU without obvious adverse effects in subcutaneous tumor.
    CONCLUSIONS: Our study revealed a specific tsRNA-GlyGCC-engaged pathway in CRC progression. Targeting tsRNA-GlyGCC in combination with 5-FU may provide a promising nanotherapeutic strategy for the treatment of 5-FU-resistance CRC.
    Keywords:  5-FU resistance; CRC; JAK1/STAT6; METTL1; SPIB; m7G; tsRNA
    DOI:  https://doi.org/10.1186/s13046-024-03132-6
  13. Pharmacogenomics. 2024 Aug 22. 1-10
    Meta-analysis revisiting the influence of UGT1A1*28 and UGT1A1*6 on irinotecan safety in colorectal cancer patients.
    Cuc Thi Thu Nguyen, Nguyen Thi Minh Thuy, Phung Thanh Huong.
      Aim: To evaluate the association between irinotecan safety and the UGT1A1 gene polymorphism in colorectal cancer (CRC) patients.Materials & methods: The studies were systematically searched and identified from three databases (PubMed, Embase and The Cochrane Library) until 28 February 2023. The relationships were evaluated using pooled odds ratio (OR).Results: A total of 30 studies out of 600 were included, comprising 4471 patients. UGT1A1*28 was associated with a statistically significant increase in the OR for diarrhea (OR: 1.59, 95% CI = 1.24-2.06 in the additive model; OR = 3.24, 95% CI = 2.01-5.21 in the recessive model; and OR = 1.95, 95% CI = 1.42-2.69 in the dominant model) and neutropenia (OR = 1.70, 95% CI = 1.40-2.06 in the additive model; OR = 4.10, 95%CI = 2.69-6.23 in the recessive model; and OR = 1.93, 95% CI = 1.61-2.31 in the dominant model). Subgroup analysis indicated consistent associations in both Asian and non-Asian populations. UGT1A1*6 was associated with a statistically significant elevation in the OR for diarrhea (only in the recessive model, OR = 2.42; 95% CI = 1.14-5.11) and neutropenia (across all genetic models).Conclusion: The UGT1A1*28 and UGT1A1*6 alleles might be a crucial indicator for predicting irinotecan safety in CRC.
    Keywords:  UGT1A1*28; UGT1A1*6; adverse events; colorectal cancer; diarrhea; irinotecan; meta-analysis; neutropenia
    DOI:  https://doi.org/10.1080/14622416.2024.2385289
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