bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024‒09‒22
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels.
  2. Growth pattern of de novo small clusters of colorectal cancer is regulated by Notch signaling at detachment.
  3. Single-cell RNA sequencing reveals the heterogeneity of MYH11+ tumour-associated fibroblasts between left-sided and right-sided colorectal cancer.
  4. c-MET is an important marker for acid-driven metastasis and anti-immune in colorectal cancer.
  5. Lipolysis-stimulated lipoprotein receptor promote lipid uptake and fatty acid oxidation in gastric cancer.
  6. Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
  7. Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.
  8. Myosin Vb Traffics P-glycoprotein to the Apical Membrane of Intestinal Epithelial Cells.
  9. Reevaluating stemness in the intestinal crypt.
  10. T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer.
  11. GPX4 restricts ferroptosis of NKp46+ILC3s to control intestinal inflammation.
  12. Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS -mutated colorectal cancer.
  13. The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer.
  14. Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer.
  1. Gastroenterology. 2024 Sep 17. pii: S0016-5085(24)05464-7. [Epub ahead of print]
    Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels.
    Jenisha Ghimire, Morgan E Collins, Patricia Snarski, Angelle N King, Emmanuelle Ruiz, Rida Iftikhar, Harrison M Penrose, Krzysztof Moroz, Tyler Rorison, Melody Baddoo, Muhammad Anas Naeem, Arnold H Zea, Scott T Magness, Erik F Flemington, Susan E Crawford, Suzana D Savkovic.
      BACKGROUND & AIMS: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aim to determine the significance of diacyltransferases, DGAT1/2, responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis.METHODS: Human colon cancer samples, colon cancer cells, colonospheres, and ApcMin/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and siRNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analyses of CUT&RUN and RNAseq data were performed.
    RESULTS: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs non-transformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and LDs accumulation, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in ApcMin/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in colon cancer patients.
    CONCLUSION: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, providing a platform for the future development of effective treatments for colon cancer patients.
    Keywords:  Colon Cancer; DGAT1; DGAT2; FOXO3; Lipid Droplets; Obesity
    DOI:  https://doi.org/10.1053/j.gastro.2024.09.011
  2. Cancer Sci. 2024 Sep 19.
    Growth pattern of de novo small clusters of colorectal cancer is regulated by Notch signaling at detachment.
    Yi-Kai Lin, Roberto Coppo, Kunishige Onuma, Hiroko Endo, Jumpei Kondo, Sadahiro Iwabuchi, Shinichi Hashimoto, Yoshiro Itatani, Kazutaka Obama, Masahiro Inoue.
      Cancer cell clusters have a higher capacity for metastasis than single cells, suggesting cancer cell clusters have biological properties different from those of single cells. The nature of de novo cancer cell clusters that are newly formed from tumor masses is largely unknown. Herein, we generated small cell clusters from colorectal cancer organoids and tracked the growth patterns of the clusters up to four cells. Growth patterns were classified into actively growing and poorly growing spheroids (PG). Notch signaling was robustly activated in small clusters immediately after dissociation, and Notch signaling inhibition markedly increased the proportion of PG spheroids. Only a limited number of PG spheroids grew under growth-permissive conditions in vitro, but xenograft tumors derived from Notch inhibited clusters showed growth rates comparable to those of untreated spheroids. Thus, de novo clusters are composed of cells with interchangeable growth fates, which are regulated in a context-dependent manner by Notch signaling.
    Keywords:  Notch; cancer cell cluster; cell fate; circulating tumor cell; inactive growth
    DOI:  https://doi.org/10.1111/cas.16299
  3. J Cell Mol Med. 2024 Sep;28(18): e70102
    Single-cell RNA sequencing reveals the heterogeneity of MYH11+ tumour-associated fibroblasts between left-sided and right-sided colorectal cancer.
    Chao Wang, Yue Zhao, Sainan Zhang, Meiyu Du, Guanzhi He, Senwei Tan, Hailong Li, Duoyi Zhang, Liang Cheng.
      Colorectal cancer (CRC) exhibits considerable heterogeneity on tumour location. However, there is still a lack of comprehensive annotation regarding the characteristics and differences between the left-sided (L-CRC) and right-sided (R-CRC) CRC. Here, we performed single-cell RNA sequencing (scRNA-seq) on immune and stromal cells from 12 L-CRC and 10 R-CRC patients. We found that L-CRC exhibited stronger tumour invasion and poor prognosis compared with R-CRC. In addition, functional enrichment analysis of a normal cohort showed that fibroblasts of left colon are associated with tumour-related pathways. This suggested that the heterogeneity observed in both L-CRC and R-CRC may be influenced by the specific location within the colon itself. Further, we identified a potentially novel MYH11+ cancer-associated fibroblast (CAF) subset predominantly enriched in L-CRC. Moreover, we found that MYH11+ CAFs may promote tumour migration via interacting with macrophages, and was associated with poor prognosis in CRC. In summary, our study revealed the crucial role of MYH11+ CAFs in predicting a poor prognosis, thereby contributing valuable insights to the exploration of heterogeneity in L-CRC and R-CRC.
    Keywords:  colorectal cancer; left‐sided and right‐sided colorectal cancer; single cell
    DOI:  https://doi.org/10.1111/jcmm.70102
  4. Int Immunopharmacol. 2024 Sep 13. pii: S1567-5769(24)01675-8. [Epub ahead of print]142(Pt A): 113153
    c-MET is an important marker for acid-driven metastasis and anti-immune in colorectal cancer.
    Xing Wan, Zhigui Li, Liming Zhou.
      BACKGROUND: The tumor microenvironment plays an important role in cancer progression, especially acidic microenvironment which distinguish cancer from normal tissues and immune microenvironment. This study was the first to investigate whether acidic microenvironment affects colorectal metastasis through MET and the relationship between MET and immune microenvironment.METHODS: We used TCGA and GEO databases to predict MET expression, its relationship with clinical features, and biological function it mediated, and validated its expression with clinical data, as well as to verify that MET mediates acidic microenvironment-induced colorectal cancer metastasis by inducing EMT at the cellular and animal levels. The TCGA database was also used to analyze the relationship between MET and immune cells, immune checkpoints and TMB in colorectal cancer, and to predict its value in prognosis and immunological treatment and targeted therapy in pan-cancer.
    RESULTS: MET is highly expressed in colorectal cancer and is associated with metastasis and prognosis. Its biological function is mainly related to adhesion, cell cycle and fatty acid metabolism, and it can mediate acidic microenvironment to induce EMT and promote metastasis. According to immunoinfiltration analysis, MET expression is correlated with CD8 + T cells, DC, macrophages, Tregs, and TMB in CRC and were associated with the prognosis, immune checkpoint, and TMB of ACC, PRAD, LUAD respectively, in pan-cancer.
    CONCLUSIONS: MET is an important contributor to acid-driven colorectal cancer metastasis and participates in immune escape of colorectal cancer. It is of great significance for the prognosis and immunotherapy of colorectal cancer and some other cancers.
    Keywords:  Colorectal cancer; Immunity; MET; Metastasis; Prognosis
    DOI:  https://doi.org/10.1016/j.intimp.2024.113153
  5. Gastric Cancer. 2024 Sep 19.
    Lipolysis-stimulated lipoprotein receptor promote lipid uptake and fatty acid oxidation in gastric cancer.
    Kota Kawabata, Tsuyoshi Takahashi, Koji Tanaka, Yukinori Kurokawa, Kazuyoshi Yamamoto, Takuro Saito, Kota Momose, Kotaro Yamashita, Tomoki Makino, Takashi Yokouchi, Kunihiko Kawai, Satoshi Serada, Minoru Fujimoto, Kiyokazu Nakajima, Tetsuji Naka, Hidetoshi Eguchi, Yuichiro Doki.
      BACKGROUND: Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer.METHODS: We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo.
    RESULTS: In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index.
    CONCLUSIONS: We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer.
    Keywords:  Fatty acid oxidation; Gastric cancer; Lipid uptake; Lipolysis-stimulated lipoprotein receptor
    DOI:  https://doi.org/10.1007/s10120-024-01552-z
  6. Dis Model Mech. 2024 Sep 01. pii: dmm050814. [Epub ahead of print]17(9):
    Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
    Patrick B Jonker, Alexander Muir.
      Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.
    Keywords:  Acidosis; Diet; Hypoxia; Lipid metabolism; Nutrient deprivation; Tumor microenvironment
    DOI:  https://doi.org/10.1242/dmm.050814
  7. Nat Genet. 2024 Sep 16.
    Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.
    Philip J Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T Harris, Maria Mandelia, Charlie Mills, Malcolm G Dunlop, Richard S Houlston.
      Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer-gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.
    DOI:  https://doi.org/10.1038/s41588-024-01900-w
  8. Gastroenterology. 2024 Sep 17. pii: S0016-5085(24)05459-3. [Epub ahead of print]
    Myosin Vb Traffics P-glycoprotein to the Apical Membrane of Intestinal Epithelial Cells.
    Sarah A Dooley, Elena Kolobova, Andreanna Burman, Izumi Kaji, Jessica R Digrazia, Rachel Stubler, Anna Goldstein, Charulekha Packirisamy, Alexander W Coutts, Milena Saqui-Salces, Nan Gao, Melinda A Engevik, Mitchell D Shub, James R Goldenring, Amy C Engevik.
      BACKGROUND & AIMS: The xenobiotic efflux pump P-glycoprotein is highly expressed on the apical membrane of the gastrointestinal tract where it regulates the levels of intracellular substrates. P-glycoprotein is altered in disease, but the mechanisms which regulate the levels of P-glycoprotein are still being explored. The molecular motor Myosin Vb (Myo5b) traffics diverse cargo to the apical membrane of intestinal epithelial cells. We hypothesized that Myo5b was responsible for delivery of P-glycoprotein to the apical membrane of enterocytes.METHODS: We used multiple murine models that lack functional Myo5b or the myosin binding partner Rab11a to analyze P-glycoprotein localization. Pig and human tissue were analyzed to determine P-glycoprotein localization in the setting of MYO5B mutations. Intestinal organoids were used to examine P-glycoprotein trafficking and to assay P-glycoprotein function when MYO5 is inhibited.
    RESULTS: In mice lacking Myo5b or the binding partner Rab11a, P-glycoprotein was improperly trafficked and had decreased presence in the brush border of enterocytes. Immunostaining of a pig model lacking functional Myo5b and human biopsies from a patient with an inactivating mutation in Myo5b also showed altered localization of intestinal P-glycoprotein. Human intestinal organoids expressing the motorless MYO5B tail domain had co-localization with P-glycoprotein, confirming that P-glycoprotein was trafficked by MYO5B in human enterocytes. Inhibition of MYO5 in human intestinal cell lines and organoids resulted in decreased P-glycoprotein capacity. Additionally, inhibition of MYO5 in human colon cancer cells diminished P-glycoprotein activity and increased cell death in response to a chemotherapeutic drug.
    CONCLUSIONS: Collectively, these data demonstrate that Myo5b is necessary for the apical delivery of P-glycoprotein.
    Keywords:  MDR1; Myosin Vb; P-glycoprotein; cell trafficking
    DOI:  https://doi.org/10.1053/j.gastro.2024.09.007
  9. Gastroenterology. 2024 Sep 13. pii: S0016-5085(24)05463-5. [Epub ahead of print]
    Reevaluating stemness in the intestinal crypt.
    Samuel Asfaha, Nicola L Jones.
      
    DOI:  https://doi.org/10.1053/j.gastro.2024.09.010
  10. iScience. 2024 Sep 20. 27(9): 110754
    T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer.
    Kelly Tran, Anita N Kumari, Dinesh Raghu, Daniel R A Cox, Su Kah Goh, Marcos V Perini, Vijayaragavan Muralidharan, Niall C Tebbutt, Andreas Behren, John Mariadason, David S Williams, Lisa A Mielke.
      The presence of precursor to exhausted (Tpex) CD8+ T cells is important to maintain robust immunity following treatment with immune checkpoint inhibition (ICI). Impressive responses to ICI are emerging in patients with stage II-III mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC). We found 64% of dMMR and 15% of mismatch repair-proficient (pMMR) stage III CRCs had a high frequency of tumor infiltrating lymphocytes (TIL-hi). Furthermore, expression of TCF-1 (Tcf7) by CD8+ T cells predicted improved patient prognosis and Tpex cells (CD3+CD8+TCF-1+PD-1+) were abundant within lymphoid aggregates of stage III CRCs. In contrast, CD3+CD8+TCF-1-PD-1+ cells were more abundant at the invasive front and tumor core, while γδ T cells were equally abundant in all tumor areas. Interestingly, no differences in the frequency of Tpex cells were observed between TIL-hi dMMR and TIL-hi pMMR CRCs. Therefore, Tpex cell function and ICI response rates in TIL-hi CRC warrants further investigation.
    Keywords:  Cancer; Components of the immune system; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2024.110754
  11. Cell Death Dis. 2024 Sep 19. 15(9): 687
    GPX4 restricts ferroptosis of NKp46+ILC3s to control intestinal inflammation.
    Xinyao Li, Junyu He, Xiang Gao, Guilang Zheng, Chunling Chen, Yimin Chen, Zhe Xing, Tianci Wang, Jian Tang, Yuxiong Guo, Yumei He.
      Group 3 innate lymphoid cells (ILC3s) are essential for both pathogen defense and tissue homeostasis in the intestine. Dysfunction of ILC3s could lead to increased susceptibility to intestinal inflammation. However, the precise mechanisms governing the maintenance of intestinal ILC3s are yet to be fully elucidated. Here, we demonstrated that ferroptosis is vital for regulating the survival of intestinal ILC3. Ferroptosis-related genes, including GPX4, a key regulator of ferroptosis, were found to be upregulated in intestinal mucosal ILC3s from ulcerative colitis patients. Deletion of GPX4 resulted in a decrease in NKp46+ILC3 cell numbers, impaired production of IL-22 and IL-17A, and exacerbated intestinal inflammation in a T cell-independent manner. Our mechanistic studies revealed that GPX4-mediated ferroptosis in NKp46+ILC3 cells was regulated by the LCN2-p38-ATF4-xCT signaling pathway. Mice lacking LCN2 in ILC3s or administration of a p38 pathway inhibitor exhibited similar phenotypes of ILC3 and colitis to those observed in GPX4 conditional knock-out mice. These observations provide novel insights into therapeutic strategies for intestinal inflammation by modulating ILC3 ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07060-3
  12. bioRxiv. 2024 Sep 06. pii: 2024.09.05.611458. [Epub ahead of print]
    Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS -mutated colorectal cancer.
    Susmita Ghosh, Fan Fan, Reid Powell, Yong Park, Clifford Stephan, E Scott Kopetz, Lee M Ellis, Rajat Bhattacharya.
      Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS -mutated mCRC.Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS -mutated mCRC.
    Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro , and we validated the efficacy of the drugs in vivo .
    Methods: HTS was performed using 3-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with 2 clinically ready libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the effects of the drugs on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts.
    Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS -mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell cycle progression and increases in microtubule stability that resulted in significantly higher defects in the mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS -mutant patient-derived xenograft mouse models.
    Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS -mutated, metastatic CRC.
    DOI:  https://doi.org/10.1101/2024.09.05.611458
  13. Oncogene. 2024 Sep 17.
    The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer.
    Wenbo Tang, Yiqing Yang, Zhuoyue Fu, Weimin Xu, Weijun Ou, Fangyuan Liu, Peng Du, Chen-Ying Liu.
      The RNA helicase DDX21 is vital for ribosome biogenesis and is upregulated in CRC, but the mechanism by which DDX21 is dysregulated and by which DDX21 promotes tumorigenesis in CRC remains poorly understood. Here, we showed that DDX21 is a direct transcriptional target gene of β-catenin and mediates the protumorigenic function of β-catenin in CRC. DDX21 expression is correlated with the expression and activity of β-catenin, and high DDX21 expression is associated with a poor prognosis in CRC patients. Loss of DDX21 leads to cytoplasmic translocation and decreased transcriptional activity of YAP and suppresses the proliferation and migration of CRC cells, which can be partially rescued by YAP reactivation. Importantly, by using translation elongation inhibitors and DNA intercalators, we showed that ribosomal stress upregulates DDX21 expression and induces the downregulation of LATS and the activation of YAP, probably through the ZAKα-MKK4/7-JNK axis. Overall, our study revealed the transcriptional activation mechanism of DDX21 in CRC and the activation of YAP in the ribosomal stress response, indicating the potential of combination therapy involving the induction of ribosomal stress and YAP inhibition.
    DOI:  https://doi.org/10.1038/s41388-024-03160-8
  14. Cell Death Dis. 2024 Sep 14. 15(9): 675
    Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer.
    Jiangli Zhu, Xize Cao, Zhenshuai Chen, Birou Lai, Lingling Xi, Jinghang Zhang, Shaohui Zhu, Shiqian Qi, Yinming Liang, Fei Cao, Binhui Zhou, Yu Song, Sheng Jiang, Tianyu Wang, Xiaohong Kang, Eryan Kong.
      Rap2b, a proto-oncogene upregulated in colorectal cancer (CRC), undergoes protein S-palmitoylation at specific C-terminus sites (C176/C177). These palmitoylation sites are crucial for Rap2b localization on the plasma membrane (PM), as mutation of C176 or C177 results in cytosolic relocation of Rap2b. Our study demonstrates that Rap2b influences cell migration and invasion in CRC cells, independent of proliferation, and this activity relies on its palmitoylation. We identify ABHD17a as the depalmitoylating enzyme for Rap2b, altering PM localization and inhibiting cell migration and invasion. EGFR/PI3K signaling regulates Rap2b palmitoylation, with PI3K phosphorylating ABHD17a to modulate its activity. These findings highlight the potential of targeting Rap2b palmitoylation as an intervention strategy. Blocking the C176/C177 sites using an interacting peptide attenuates Rap2b palmitoylation, disrupting PM localization, and suppressing CRC metastasis. This study offers insights into therapeutic approaches targeting Rap2b palmitoylation for the treatment of metastatic CRC, presenting opportunities to improve patient outcomes.
    DOI:  https://doi.org/10.1038/s41419-024-07061-2
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