bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–06–30
sixteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Drug-Resistance Biomarkers in Patient-Derived Colorectal Cancer Organoid and Fibroblast Co-Culture System.
  2. An iPSC-derived small intestine-on-chip with self-organizing epithelial, mesenchymal, and neural cells.
  3. Exploring the potential of human intestinal organoids: Applications, challenges, and future directions.
  4. ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.
  5. The tumor immune microenvironment and T-cell-related immunotherapies in colorectal cancer.
  6. FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.
  7. Cancer stem cell mimicry for immune evasion and therapeutic resistance.
  8. β-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo.
  9. Downregulation of chemoresistance by claudin-14 silencing in human colorectal cancer cells.
  10. Enterocyte-specific FATP4 deficiency elevates blood lipids via a shift from polar to neutral lipids in distal intestine.
  11. Differences in the molecular organisation of tumours along the colon are linked to interactions within the tumour ecosystem.
  12. Profile of matrix-entrapped extracellular vesicles of microenvironmental and infiltrating cell origin in decellularized colorectal cancer and adjacent mucosa.
  13. RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer.
  14. NAT1 inhibits liver metastasis of colorectal cancer by regulating EMT and glycolysis.
  15. MEX3A promotes colorectal cancer migration, invasion and EMT via regulating the Wnt/β-catenin signaling pathway.
  16. TGFβ in pancreas and colorectal cancer: opportunities to overcome therapeutic resistance.
  1. Curr Issues Mol Biol. 2024 Jun 11. 46(6): 5794-5811
    Drug-Resistance Biomarkers in Patient-Derived Colorectal Cancer Organoid and Fibroblast Co-Culture System.
    Kyoung-Bin Ryu, Jeong-Ah Seo, Kyerim Lee, Juhyun Choi, Geon Yoo, Ji-Hye Ha, Mee Ryung Ahn.
      Colorectal cancer, the third most commonly occurring tumor worldwide, poses challenges owing to its high mortality rate and persistent drug resistance in metastatic cases. We investigated the tumor microenvironment, emphasizing the role of cancer-associated fibroblasts in the progression and chemoresistance of colorectal cancer. We used an indirect co-culture system comprising colorectal cancer organoids and cancer-associated fibroblasts to simulate the tumor microenvironment. Immunofluorescence staining validated the characteristics of both organoids and fibroblasts, showing high expression of epithelial cell markers (EPCAM), colon cancer markers (CK20), proliferation markers (KI67), and fibroblast markers (VIM, SMA). Transcriptome profiling was conducted after treatment with anticancer drugs, such as 5-fluorouracil and oxaliplatin, to identify chemoresistance-related genes. Changes in gene expression in the co-cultured colorectal cancer organoids following anticancer drug treatment, compared to monocultured organoids, particularly in pathways related to interferon-alpha/beta signaling and major histocompatibility complex class II protein complex assembly, were identified. These two gene groups potentially mediate drug resistance associated with JAK/STAT signaling. The interaction between colorectal cancer organoids and fibroblasts crucially modulates the expression of genes related to drug resistance. These findings suggest that the interaction between colorectal cancer organoids and fibroblasts significantly influences gene expression related to drug resistance, highlighting potential biomarkers and therapeutic targets for overcoming chemoresistance. Enhanced understanding of the interactions between cancer cells and their microenvironment can lead to advancements in personalized medical research..
    Keywords:  cancer-associated fibroblast; co-culture; drug resistance; interferon-alpha/beta signaling; major histocompatibility complex class II; tumor microenvironment
    DOI:  https://doi.org/10.3390/cimb46060346
  2. Cell Rep. 2024 Jun 20. pii: S2211-1247(24)00575-8. [Epub ahead of print]43(7): 114247
    An iPSC-derived small intestine-on-chip with self-organizing epithelial, mesenchymal, and neural cells.
    Renée Moerkens, Joram Mooiweer, Aarón D Ramírez-Sánchez, Roy Oelen, Lude Franke, Cisca Wijmenga, Robert J Barrett, Iris H Jonkers, Sebo Withoff.
      Human induced pluripotent stem cell (hiPSC)-derived intestinal organoids are valuable tools for researching developmental biology and personalized therapies, but their closed topology and relative immature state limit applications. Here, we use organ-on-chip technology to develop a hiPSC-derived intestinal barrier with apical and basolateral access in a more physiological in vitro microenvironment. To replicate growth factor gradients along the crypt-villus axis, we locally expose the cells to expansion and differentiation media. In these conditions, intestinal epithelial cells self-organize into villus-like folds with physiological barrier integrity, and myofibroblasts and neurons emerge and form a subepithelial tissue in the bottom channel. The growth factor gradients efficiently balance dividing and mature cell types and induce an intestinal epithelial composition, including absorptive and secretory lineages, resembling the composition of the human small intestine. This well-characterized hiPSC-derived intestine-on-chip system can facilitate personalized studies on physiological processes and therapy development in the human small intestine.
    Keywords:  CP: Stem cell research; differentiation medium; enteric neuron; gut-on-chip; human; induced pluripotent stem cell; intestinal epithelial barrier; intestine-on-chip; mesenchyme; organ-on-chip; small intestine
    DOI:  https://doi.org/10.1016/j.celrep.2024.114247
  3. Life Sci. 2024 Jun 26. pii: S0024-3205(24)00465-X. [Epub ahead of print] 122875
    Exploring the potential of human intestinal organoids: Applications, challenges, and future directions.
    Inês A Parente, Linda Chiara, Simona Bertoni.
      The complex and dynamic environment of the gastrointestinal tract shapes one of the fastest renewing tissues in the human body, the intestinal epithelium. Considering the lack of human preclinical studies, reliable models that mimic the intestinal environment are increasingly explored. Patient-derived intestinal organoids are powerful tools that recapitulate in vitro many pathophysiological features of the human intestine. In this review, the possible applications of human intestinal organoids in different research fields are highlighted. From physiologically relevant to intestinal disease modeling, regenerative medicine, and toxicology studies, the potential of intestinal organoids will be here presented and discussed. Despite the remarkable opportunities offered, limitations related to ethical concerns, tissue collection, reproducibility, and methodologies may hinder the full exploitation of this cell-based model into high throughput studies and clinical practice. Currently, distinct approaches can be used to overcome the numerous challenges found along the way and to allow the full implementation of this ground-breaking technology.
    Keywords:  Drug screening; Intestinal toxicology; Precision medicine; Preclinical in vitro model; Regenerative medicine; Stem cells
    DOI:  https://doi.org/10.1016/j.lfs.2024.122875
  4. EMBO Rep. 2024 Jun 27.
    ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.
    Constantin Menche, Harald Schuhwerk, Isabell Armstark, Pooja Gupta, Kathrin Fuchs, Ruthger van Roey, Mohammed H Mosa, Anne Hartebrodt, Yussuf Hajjaj, Ana Clavel Ezquerra, Manoj K Selvaraju, Carol I Geppert, Stefanie Bärthel, Dieter Saur, Florian R Greten, Simone Brabletz, David B Blumenthal, Andreas Weigert, Thomas Brabletz, Henner F Farin, Marc P Stemmler.
      The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers are reduced. Single-cell transcriptomics, histological characterization, and in vitro modeling reveal a crucial role of ZEB1 in CAF polarization, promoting myofibroblastic features by restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases NFκB-mediated cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, offering a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.
    Keywords:  Cancer-Associated Fibroblast Plasticity; Colorectal Cancer; Immune Checkpoint Blockade; Tumor Microenvironment
    DOI:  https://doi.org/10.1038/s44319-024-00186-7
  5. Discov Oncol. 2024 Jun 25. 15(1): 244
    The tumor immune microenvironment and T-cell-related immunotherapies in colorectal cancer.
    Liu Chuang, Ju Qifeng, Yu Shaolei.
      The tumor microenvironment includes a complex network of immune T-cell subsets that play important roles in colorectal cancer (CRC) progression and are key elements of CRC immunotherapy. T cells develop and migrate within tumors, recognizing tumor-specific antigens to regulate immune surveillance. Current immunotherapies are divided into the following main categories based on the regulatory role of T-cell subsets in the tumor immune microenvironment (TIME): cytokines, monoclonal antibodies, peptide vaccines, CAR-T cells and more. This review describes the composition of the tumor immune microenvironment in colorectal cancer and the involvement of T cells in the pathogenesis and progression of CRC as well as current T-cell-related immunotherapies. Further studies on CRC-specific tumor antigens, the gene regulation of T cells, and the regulation of immune activity are needed.
    Keywords:  CAR-T; Colorectal cancer; Monoclonal antibody; T cell; Tumor immune microenvironment
    DOI:  https://doi.org/10.1007/s12672-024-01117-7
  6. Elife. 2024 Jun 26. pii: RP94605. [Epub ahead of print]13
    FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.
    Chenxi Gao, Huaibin Ge, Shih-Fan Kuan, Chunhui Cai, Xinghua Lu, Farzad Esni, Robert E Schoen, Jing H Wang, Edward Chu, Jing Hu.
      BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.
    Keywords:  BRAFV600E; EGFR; ERK; FAK; cancer biology; carcinogenesis; mouse
    DOI:  https://doi.org/10.7554/eLife.94605
  7. Cell Stem Cell. 2024 Jun 16. pii: S1934-5909(24)00211-X. [Epub ahead of print]
    Cancer stem cell mimicry for immune evasion and therapeutic resistance.
    Phei Er Saw, Qiang Liu, Ping-Pui Wong, Erwei Song.
      Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
    Keywords:  cancer stem cells; immunotherapeutic resistance; immunotherapy; mimicry
    DOI:  https://doi.org/10.1016/j.stem.2024.06.003
  8. Mol Med. 2024 Jun 23. 30(1): 95
    β-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo.
    Meng Deng, Peijie Yan, Hui Gong, Guiqiu Li, Jianjie Wang.
       BACKGROUND: Ketone β-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof.
    METHODS: CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro.
    RESULTS: Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function.
    CONCLUSIONS: β-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.
    Keywords:  Colorectal cancer; Drug resistance; H3K79me; Oxaliplatin; Β-hydroxybutyrate
    DOI:  https://doi.org/10.1186/s10020-024-00864-1
  9. Arch Biochem Biophys. 2024 Jun 26. pii: S0003-9861(24)00196-6. [Epub ahead of print] 110075
    Downregulation of chemoresistance by claudin-14 silencing in human colorectal cancer cells.
    Yuko Mizukami, Ayaka Ito, Shotaro Hashimoto, Tomoka Ando, Yoshinobu Ishikawa, Hiroaki Eguchi, Yuta Yoshino, Toshiyuki Matsunaga, Akira Ikari.
      An exceptional expression of claudins (CLDNs), tight junction (TJ) proteins, is observed in various solid cancer tissues. However, the pathophysiological roles of CLDNs have not been clarified in detail. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and cultured cancer epithelial cells. We found CLDN14 silencing decreased cell viability without affecting spheroid size in the three-dimensional (3D) spheroid model of DLD-1 cells derived from human CRC. Mitochondria activity and oxidative stress level were reduced by CLDN14 silencing. Furthermore, CLDN14 silencing decreased the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target antioxidative genes. CLDN14 was colocalized with ZO-1, a scaffolding protein in the TJ. CLDN14 silencing induced the disruption of TJ barrier such as the reduction of transepithelial electrical resistance and elevation of fluxes of small molecules including glucose in two-dimensional (2D) cultured model,. The depletion of glucose induced the elevation of ROS generation, mitochondria activity, and Nrf2 expression. These results suggest that CLDN14 increases Nrf2 expression in spheroids mediated via the formation of paracellular barrier to glucose. The cytotoxicities of doxorubicin, an anthracycline anticancer drug, and oxaliplatin, a platinum-based agent, were augmented by an Nrf2 activator in 2D cultured cells. The anticancer drug-induced toxicity was enhanced by CLDN14 silencing in 3D spheroids. We suggest that CLDN14 may potentiate chemoresistance mediated by the suppression of paracellular glucose permeability and activation of the Nrf2 signaling pathway in CRC cells.
    Keywords:  chemoresistance; claudin-14; colorectal cancer
    DOI:  https://doi.org/10.1016/j.abb.2024.110075
  10. Am J Physiol Gastrointest Liver Physiol. 2024 Jun 25.
    Enterocyte-specific FATP4 deficiency elevates blood lipids via a shift from polar to neutral lipids in distal intestine.
    Jessica Seeßle, Gerhard Liebisch, Simone Staffer, Sabine Tuma-Kellner, Uta Merle, Thomas Herrmann, Walee Chamulitrat.
      FATP4 was thought to mediate intestinal lipid absorption which was disputed by a study using keratinocyte-Fatp4-rescued Fatp4-/- mice. These knockouts when fed with a western diet showed elevated intestinal triglyceride (TG) and fatty-acid levels. To investigate a possible role of FATP4 on intestinal lipid processing, ent-Fatp4 (KO) mice were generated by Villin-Cre-specific inactivation of the Fatp4 gene. We aimed to measure circulating and intestinal lipids in control and KO mice after acute or chronic fat intake or during ageing. Remarkably, ent-Fatp4 mice displayed a ~30% decrease in ileal behenic, lignoceric, and nervonic acids, ceramides containing these FA, as well as, ileal sphingomyelin, phosphatidylcholine, and phosphatidylinositol levels. Such decreases were concomitant with an increase in jejunal cholesterol ester. After 2-week recovery from high lipid overload by tyloxapol and oral-lipid treatment, ent-Fatp4 mice showed an increase in plasma TG and chylomicrons. Upon overnight fasting followed by an oral fat meal, ent-Fatp4 mice showed an increase in plasma TG-rich lipoproteins and particle number of chylomicrons and very low-density lipoproteins. During ageing or after feeding with a high-fat high-cholesterol (HFHC) diet, ent-Fatp4 mice showed an increase in plasma TG, fatty acids, glycerol, and lipoproteins as well as intestinal lipids. HFHC-fed KO mice displayed an increase in body weights, the numbers of lipid droplets with larger sizes in the ileum concomitant with a decrease in ileal ceramides and phosphatidylcholine. Thus, enterocyte FATP4 deficiency led to a metabolic shift from polar to neutral lipids in distal intestine rendering an increase in plasma lipids and lipoproteins.
    Keywords:  ageing; fat absorption; fatty acid transport proteins; high-fat high-cholesterol diets; lipoprotiens
    DOI:  https://doi.org/10.1152/ajpgi.00109.2024
  11. Biochim Biophys Acta Mol Basis Dis. 2024 Jun 21. pii: S0925-4439(24)00304-1. [Epub ahead of print] 167311
    Differences in the molecular organisation of tumours along the colon are linked to interactions within the tumour ecosystem.
    Tiziano Dallavilla, Serena Galiè, Gaia Sambruni, Simona Borin, Nicola Fazio, Uberto Fumagalli-Romario, Teresa Manzo, Luigi Nezi, Martin H Schaefer.
      Tumours exhibit significant heterogeneity in their molecular profiles across patients, largely influenced by the tissue of origin, where certain driver gene mutations are predominantly associated with specific cancer types. Here, we unveil an additional layer of complexity: some cancer types display anatomic location-specific mutation profiles akin to tissue-specificity. To better understand this phenomenon, we concentrate on colon cancer. While prior studies have noted changes of the frequency of molecular alterations along the colon, the underlying reasons and whether those changes occur rather gradual or are distinct between the left and right colon, remain unclear. Developing and leveraging stringent statistical models on molecular data from 522 colorectal tumours from The Cancer Genome Atlas, we reveal disparities in molecular properties between the left and right colon affecting many genes. Interestingly, alterations in genes responsive to environmental cues and properties of the tumour ecosystem, including metabolites which we quantify in a cohort of 27 colorectal cancer patients, exhibit continuous trends along the colon. Employing network methodologies, we uncover close interactions between metabolites and genes, including drivers of colon cancer, showing continuous abundance or alteration profiles. This underscores how anatomic biases in the composition and interactions within the tumour ecosystem help explaining gradients of carcinogenesis along the colon.
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167311
  12. J Extracell Biol. 2024 Mar;3(3): e144
    Profile of matrix-entrapped extracellular vesicles of microenvironmental and infiltrating cell origin in decellularized colorectal cancer and adjacent mucosa.
    Sarah Tassinari, Edoardo D'Angelo, Federico Caicci, Cristina Grange, Jacopo Burrello, Matteo Fassan, Alessia Brossa, Riccardo Quoc Bao, Gaya Spolverato, Marco Agostini, Federica Collino, Benedetta Bussolati.
      Cellular elements that infiltrate and surround tumours and pre-metastatic tissues have a prominent role in tumour invasion and growth. The extracellular vesicles specifically entrapped and stored within the extracellular matrix (ECM-EVs) may reflect the different populations of the tumour microenvironment and their change during tumour progression. However, their profile is at present unknown. To elucidate this aspect, we isolated and characterized EVs from decellularized surgical specimens of colorectal cancer and adjacent colon mucosa and analyzed their surface marker profile. ECM-EVs in tumours and surrounding mucosa mainly expressed markers of lymphocytes, natural killer cells, antigen-presenting cells, and platelets, as well as epithelial cells, representing a multicellular microenvironment. No difference in surface marker expression was observed between tumour and mucosa ECM-EVs in stage II-III tumours. At variance, in the colon mucosa adjacent to stage IV carcinomas, ECM-EV profile showed a significantly increased level of immune, epithelial and platelet markers in comparison to the matrix of the corresponding tumour. The increase of EVs from immune cells and platelets was not observed in the mucosa adjacent to low-stage tumours. In addition, CD25, a T-lymphocyte marker, resulted specifically overexpressed by ECM-EVs from stage IV carcinomas, possibly correlated with the pro-tolerogenic environment found in the corresponding tumour tissue. These results outline the tissue microenvironmental profile of EVs in colorectal carcinoma-derived ECM and unveil a profound change in the healthy mucosa adjacent to high-stage tumours.
    Keywords:  biomarkers; colorectal cancer; decellularized tissues; extracellular matrix; tumour infiltration; tumour invasion; tumour microenvironment
    DOI:  https://doi.org/10.1002/jex2.144
  13. J Extracell Biol. 2024 Feb;3(2): e141
    RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer.
    Yu-Chan Chang, Yi-Fang Yang, Chien-Hsiu Li, Ming-Hsien Chan, Meng-Lun Lu, Ming-Huang Chen, Chi-Long Chen, Michael Hsiao.
      Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, RAB31-induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.
    Keywords:  AGR2; RAB31; colon cancer; epithelial‐mesenchymal transition; oxaliplatin resistance
    DOI:  https://doi.org/10.1002/jex2.141
  14. Aging (Albany NY). 2024 Jun 24. 16
    NAT1 inhibits liver metastasis of colorectal cancer by regulating EMT and glycolysis.
    Wang Gu, Chen Li, Tingting Shen, Li Tong, Wenkang Yuan, Xiaofei Zheng, Tianqi Wang, Siyu Wang, Benshuai Zhu, Chong Zhang, Chao Zhang.
      Metastasis is the primary cause of cancer-related deaths, and colorectal cancer (CRC) liver metastasis is a major poor prognostic factor in CRC. NAT1 (N-acetyltransferase 1) plays a crucial role in the invasive and metastatic processes of colorectal cancer. The role and molecular mechanism of NAT1 on tumor cells were verified by establishing a cell model of overexpression and knockdown of NAT1, and further verified by establishing a liver metastasis model of colorectal cancer for animal experiments. In vivo and in vitro experiments have demonstrated that overexpression of NAT1 reduces the ability of metastasis and invasion of colorectal cancer cells. NAT1 overexpression inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing the EMT (epithelial-mesenchymal transition) process and glycolytic ability of tumor cells. Additionally, decreased glycolytic ability results in reduced VEGF (Vascular endothelial growth factor) expression in colorectal cancer cells. The decreased VEGF expression leads to decreased angiogenesis and vascular permeability in liver metastases, ultimately reducing the occurrence of liver metastasis. Our findings highlight that overexpression of NAT1 significantly inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing EMT, glycolytic ability, and VEGF expression in colorectal cancer cells, collectively preventing the development of liver metastasis.
    Keywords:  NAT1; VEGF; colorectal cancer (CRC); epithelial-mesenchymal transition (EMT); glycolysis; liver metastasis
    DOI:  https://doi.org/10.18632/aging.205957
  15. J Cancer Res Clin Oncol. 2024 Jun 25. 150(6): 319
    MEX3A promotes colorectal cancer migration, invasion and EMT via regulating the Wnt/β-catenin signaling pathway.
    Jiannan Xu, Songyao Chen, Tengfei Hao, Guangyao Liu, Kai Zhang, Changhua Zhang, Yulong He.
       BACKGROUND: Mex-3 RNA binding family members are well-established to be important in cancer development and progression. However, the functions of Mex-3 RNA binding family member A (MEX3A) in colorectal cancer (CRC) metastasis remain poorly understood. In this study, we aim to reveal the function and the mechanism of MEX3A in promoting CRC metastasis.
    METHODS: We used multiple databases including TCGA database, UALCAN, LinkedOmics, CancerSEA, GeneMANIA and STRING database to investigate the expression, the functions and underlying molecular mechanism of MEX3A in CRC. Multiple experimental methods were adapted to determine the study, including real-time PCR (qPCR), immunohistochemistry (IHC), western blot (WB), transfection, transwell migration and invasion assays, immunofluorescence (IF).
    RESULTS: We found that MEX3A was significantly upregulated and correlated to tumor stage and lymph nodal metastasis in CRC through bioinformatics analysis and tissue immunohistochemistry (IHC). The higher expression of MEX3A in CRC correlated with poor recurrence-free survival (RFS) and overall survival (OS). In vitro studies showed that knockdown of MEX3A suppressed EMT transition, invasion and metastasis of CRC cells. Mechanistically, we revealed that MEX3A promotes epithelial-mesenchymal transition (EMT), invasion and metastasis of CRC cells by upregulating the Wnt/β-catenin signaling pathway.
    CONCLUSION: In conclusion, our study reveals that MEX3A promotes CRC migration, invasion and EMT via regulating the Wnt/β-catenin signaling pathway and could be a novel therapeutic target for this patient population.
    Keywords:  Colorectal cancer; EMT; MEX3A; Metastasis; Wnt/β-catenin
    DOI:  https://doi.org/10.1007/s00432-024-05845-9
  16. Clin Cancer Res. 2024 Jun 25.
    TGFβ in pancreas and colorectal cancer: opportunities to overcome therapeutic resistance.
    Allan M Johansen, Steven D Forsythe, Callum Thomas McGrath, Grayson Barker, Hugo Jimenez, Ravi K Paluri, Boris C Pasche.
      TGFβ is a pleiotropic signaling pathway, which plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in CRC and pancreatic cancer, altering the tumor microenvironment, immune system, and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemo- and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-0468
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