bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–05–05
fiveteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies.
  2. A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin.
  3. Orthotopic MC-38 Allograft as a Robust Preclinical Model of Colorectal Carcinoma.
  4. Targeting the EGFR signalling pathway in metastatic colorectal cancer.
  5. MAPKAP1 orchestrates macrophage polarization and lipid metabolism in fatty liver-enhanced colorectal cancer.
  6. High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model.
  7. Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids.
  8. CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity.
  9. Hallmarks of cancer stemness.
  10. Protocol for generating and analyzing organ-on-chip using human and mouse intestinal organoids.
  11. Mesenchymal stromal/stem cells promote intestinal epithelium regeneration after chemotherapy-induced damage.
  12. Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside.
  13. Independent transcriptional patterns reveal biological processes associated with disease-free survival in early colorectal cancer.
  14. Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
  15. Identification of differentially expressed genes and splicing events in early-onset colorectal cancer.
  1. Cell Death Dis. 2024 May 01. 15(5): 306
    Impact of the thyroid hormone T3 and its nuclear receptor TRα1 on colon cancer stem cell phenotypes and response to chemotherapies.
    Maria Virginia Giolito, Serguei Bodoirat, Theo La Rosa, Mathieu Reslinger, Gabriela D A Guardia, Jana Mourtada, Leo Claret, Alain Joung, Pedro A F Galante, Luiz O F Penalva, Michelina Plateroti.
      Colorectal cancers (CRCs) are highly heterogeneous and show a hierarchical organization, with cancer stem cells (CSCs) responsible for tumor development, maintenance, and drug resistance. Our previous studies showed the importance of thyroid hormone-dependent signaling on intestinal tumor development and progression through action on stem cells. These results have a translational value, given that the thyroid hormone nuclear receptor TRα1 is upregulated in human CRCs, including in the molecular subtypes associated with CSC features. We used an established spheroid model generated from the human colon adenocarcinoma cell line Caco2 to study the effects of T3 and TRα1 on spheroid formation, growth, and response to conventional chemotherapies. Our results show that T3 treatment and/or increased TRα1 expression in spheroids impaired the response to FOLFIRI and conferred a survival advantage. This was achieved by stimulating drug detoxification pathways and increasing ALDH1A1-expressing cells, including CSCs, within spheroids. These results suggest that clinical evaluation of the thyroid axis and assessing TRα1 levels in CRCs could help to select optimal therapeutic regimens for patients with CRC. Proposed mechanism of action of T3/TRα1 in colon cancer spheroids. In the control condition, TRα1 participates in maintaining homeostatic cell conditions. The presence of T3 in the culture medium activates TRα1 action on target genes, including the drug efflux pumps ABCG2 and ABCB1. In the case of chemotherapy FOLFIRI, the increased expression of ABC transcripts and proteins induced by T3 treatment is responsible for the augmented efflux of 5-FU and Irinotecan from the cancer cells. Taken together, these mechanisms contribute to the decreased efficacy of the chemotherapy and allow cells to escape the treatment. Created with BioRender.com .
    DOI:  https://doi.org/10.1038/s41419-024-06690-x
  2. Nat Commun. 2024 Apr 27. 15(1): 3595
    A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin.
    Wei Gu, Xiaofeng Huang, Pratik N P Singh, Sanlan Li, Ying Lan, Min Deng, Lauretta A Lacko, Jesus M Gomez-Salinero, Shahin Rafii, Michael P Verzi, Ramesh A Shivdasani, Qiao Zhou.
      Plasticity among cell lineages is a fundamental, but poorly understood, property of regenerative tissues. In the gut tube, the small intestine absorbs nutrients, whereas the colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screening, we identify MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrains colonic plasticity. MTA2 loss in the adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-occupies DNA with HNF4A, an activating pan-intestinal transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic chromatin, and accumulation on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through an HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages, and their release unleashes plasticity.
    DOI:  https://doi.org/10.1038/s41467-024-47738-y
  3. Methods Mol Biol. 2024 ;2806 197-207
    Orthotopic MC-38 Allograft as a Robust Preclinical Model of Colorectal Carcinoma.
    Marina H Yakou, Shoukat Afshar-Sterle, Matthias Ernst, Lisa A Mielke.
      Colorectal cancer (CRC) is a significant global health concern, requiring effective preclinical models for studying its development and testing therapies. Mouse models have been used, including spontaneous tumors, carcinogen exposure, and tumor cell implantation as xenografts or at orthotopic sites. Here, we describe an orthotopic preclinical model of CRC, which provides a valuable tool for studying tumor growth and the tumor microenvironment, offering a more accurate representation of human CRC compared to xenograft models.
    Keywords:  Cancer; Colonoscopy; Colorectal cancer; Colorectal carcinoma; Orthotopic MC-38 allograft
    DOI:  https://doi.org/10.1007/978-1-0716-3858-3_14
  4. Lancet Gastroenterol Hepatol. 2024 Apr 29. pii: S2468-1253(23)00479-X. [Epub ahead of print]
    Targeting the EGFR signalling pathway in metastatic colorectal cancer.
    Stefania Napolitano, Giulia Martini, Davide Ciardiello, Sara Del Tufo, Erika Martinelli, Teresa Troiani, Fortunato Ciardiello.
      Epidermal growth factor receptor (EGFR) and its activated downstream signalling pathways play a crucial role in colorectal cancer development and progression. After four decades of preclinical, translational, and clinical research, it has been shown that blocking the EGFR signalling pathway at different molecular levels represents a fundamental therapeutic strategy for patients with metastatic colorectal cancer. Nevertheless, the efficacy of molecularly targeted therapies is inescapably limited by the insurgence of mechanisms of acquired cancer cell resistance. Thus, in the era of precision medicine, a deeper understanding of the complex molecular landscape of metastatic colorectal cancer is required to deliver the best treatment choices to all patients. Major efforts are currently ongoing to improve patient selection, improve the efficacy of available treatments targeting the EGFR pathway, and develop novel combination strategies to overcome therapy resistance within the continuum of care of metastatic colorectal cancer.
    DOI:  https://doi.org/10.1016/S2468-1253(23)00479-X
  5. Transl Oncol. 2024 Apr 30. pii: S1936-5233(24)00068-8. [Epub ahead of print]45 101941
    MAPKAP1 orchestrates macrophage polarization and lipid metabolism in fatty liver-enhanced colorectal cancer.
    Bo Huang, Zhenqiu Yu, Dejun Cui, Fawang Du.
      Various factors, including fatty liver and macrophage alterations, influence colorectal cancer (CRC). This study explores the mechanistic role of fatty liver in CRC progression, focusing on macrophage polarization and lipid metabolism. A murine fatty liver model was created with a high-fat diet (HFD), and CRC was induced using AOM and DSS. Single-cell transcriptome sequencing (scRNA-seq) identified MAPKAP1 as a critical gene promoting CRC via M2 macrophage polarization and lipid metabolism reprogramming. Prognosis analysis on the TCGA-CRC dataset confirmed MAPKAP1's significance. In vitro and in vivo experiments demonstrated that EVs from fatty liver cells enhanced MAPKAP1 expression, accelerating CRC development and metastasis. HFD exacerbated CRC, but fatty acid inhibitors delayed progression. Fatty liver upregulates MAPKAP1, driving M2 macrophage polarization and lipid metabolism changes, worsening CRC. These findings suggest potential therapeutic strategies for CRC, particularly targeting lipid metabolism and macrophage-mediated tumor promotion.
    Keywords:  Colorectal cancer; Extracellular vesicles; Fatty liver; Lipid metabolism; Macrophage polarization; Mapkap1
    DOI:  https://doi.org/10.1016/j.tranon.2024.101941
  6. BMC Mol Cell Biol. 2024 Apr 30. 25(1): 14
    High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model.
    Itsuma Nagao, Yoko M Ambrosini.
       BACKGROUND: Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5 + intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between palmitic acid (PA), cell proliferation, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction.
    RESULTS: Canine colonoids were subjected to PA exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of cell proliferative activity. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group.
    CONCLUSIONS: By employing canine intestinal organoid systems, we provide compelling insights into the impact of PA on intestinal physiology. These findings underscore the importance of considering both cell proliferative activity and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.
    Keywords:  Canine; High-fat diet; Intestinal organoids; Palmitic acid
    DOI:  https://doi.org/10.1186/s12860-024-00512-w
  7. Cell Death Dis. 2024 Apr 29. 15(4): 301
    Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids.
    Pilar Bustamante-Madrid, Antonio Barbáchano, David Albandea-Rodríguez, Javier Rodríguez-Cobos, Nuria Rodríguez-Salas, Isabel Prieto, Aurora Burgos, Jaime Martínez de Villarreal, Francisco X Real, José Manuel González-Sancho, María Jesús Larriba, Miguel Lafarga, Alberto Muñoz, Asunción Fernández-Barral.
      Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide an unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using colon organoids generated from healthy tissue of colorectal cancer patients. Culture of these organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1, FABP2) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the γ-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 showing only weak signals of cell differentiation, and were unresponsive to DBZ. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of BMP4 and DBZ on colon normal organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness features.
    DOI:  https://doi.org/10.1038/s41419-024-06680-z
  8. EMBO Mol Med. 2024 Apr 29.
    CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity.
    Yao Xiang, Jorge Mata-Garrido, Yuanji Fu, Christophe Desterke, Eric Batsché, Ahmed Hamaï, Christine Sedlik, Youssouf Sereme, David Skurnik, Abdelali Jalil, Rachel Onifarasoaniaina, Eric Frapy, Jean-Christophe Beche, Razack Alao, Eliane Piaggio, Laurence Arbibe, Yunhua Chang.
      As an important immune stimulator and modulator, IFNγ is crucial for gut homeostasis and its dysregulation links to diverse colon pathologies, such as colitis and colorectal cancer (CRC). Here, we demonstrated that the epigenetic regulator, CBX3 (also known as HP1γ) antagonizes IFNγ signaling in the colon epithelium by transcriptionally repressing two critical IFNγ-responsive genes: STAT1 and CD274 (encoding Programmed death-ligand 1, PD-L1). Accordingly, CBX3 deletion resulted in chronic mouse colon inflammation, accompanied by upregulated STAT1 and CD274 expressions. Chromatin immunoprecipitation indicated that CBX3 tethers to STAT1 and CD274 promoters to inhibit their expression. Reversely, IFNγ significantly reduces CBX3 binding to these promoters and primes gene expression. This antagonist effect between CBX3 and IFNγ on STAT1/PD-L1 expression was also observed in CRC. Strikingly, CBX3 deletion heightened CRC cells sensitivity to IFNγ, which ultimately enhanced their chemosensitivity under IFNγ stimulation in vitro with CRC cells and in vivo with a syngeneic mouse tumor model. Overall, this work reveals that by negatively tuning IFNγ-stimulated immune genes' transcription, CBX3 participates in modulating colon inflammatory response and CRC chemo-resistance.
    Keywords:  CBX3 (HP1γ); Colon; Colorectal Cancer; IFNγ Signaling; Inflammatory/Immune Response
    DOI:  https://doi.org/10.1038/s44321-024-00066-6
  9. Cell Stem Cell. 2024 May 02. pii: S1934-5909(24)00131-0. [Epub ahead of print]31(5): 617-639
    Hallmarks of cancer stemness.
    Jia-Jian Loh, Stephanie Ma.
      Cancer stemness is recognized as a key component of tumor development. Previously coined "cancer stem cells" (CSCs) and believed to be a rare population with rigid hierarchical organization, there is good evidence to suggest that these cells exhibit a plastic cellular state influenced by dynamic CSC-niche interplay. This revelation underscores the need to reevaluate the hallmarks of cancer stemness. Herein, we summarize the techniques used to identify and characterize the state of these cells and discuss their defining and emerging hallmarks, along with their enabling and associated features. We also highlight potential future directions in this field of research.
    Keywords:  cancer cell plasticity; cancer stem cells; cancer stemness; immunosuppression; metastasis; self-renewal; tumor microenvironment; tumor recurrence; tumor-initiating cells
    DOI:  https://doi.org/10.1016/j.stem.2024.04.004
  10. STAR Protoc. 2024 Apr 25. pii: S2666-1667(24)00202-8. [Epub ahead of print]5(2): 103037
    Protocol for generating and analyzing organ-on-chip using human and mouse intestinal organoids.
    Inga Viktoria Hensel, Michelle Steinhauer, Richard Fairless, Martin Resnik-Docampo.
      Organ-on-chip technology is a powerful tool for in vitro modeling. Combining it with organoids overcomes lumen inaccessibility while preserving cellular diversity and function of the intestinal epithelium. Here, we present a protocol for generating and analyzing organ-on-chips using human and mouse intestinal organoids. This protocol covers organoid line establishment, single-cell dissociation, chip preparation, and seeding. It outlines procedures for permeability assays, RNA isolation, staining, and imaging. Additionally, we describe independent stimulation and sampling of the apical and basal side.
    Keywords:  cell Biology; cell culture; cell isolation; cell-based assays; organoids; tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2024.103037
  11. Stem Cell Res Ther. 2024 Apr 29. 15(1): 125
    Mesenchymal stromal/stem cells promote intestinal epithelium regeneration after chemotherapy-induced damage.
    B Yetkin-Arik, S A Jansen, S Varderidou-Minasian, B Westendorp, K-P Skarp, M Altelaar, C A Lindemans, M J Lorenowicz.
       BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is hampered by occurrence of acute graft-versus-host disease (aGvHD); an inflammatory response damaging recipient organs, with gut, liver, and skin being the most susceptible. Intestinal GvHD injury is often a life-threatening complication in patients unresponsive to steroid treatment. Allogeneic mesenchymal stromal/stem cell (MSC) infusions are a promising potential treatment for steroid-resistant aGvHD. Data from our institution and others demonstrate rescue of approximately 40-50% of aGvHD patients with MSCs in Phase I, II studies and minor side effects. Although promising, better understanding of MSC mode of action and patient response to MSC-based therapy is essential to improve this lifesaving treatment.
    METHODS: Single cell human small intestine organoids were embedded in Matrigel, grown for 5 days and treated with busulfan for 48 h. Organoids damaged by treatment with busulfan or control organoids were co-cultured with 5000, 10,000, and 50,000 MSCs for 24 h, 48 h or 7 days and the analyses such as surface area determination, proliferation and apoptosis assessment, RNA sequencing and proteomics were performed.
    RESULTS: Here, we developed a 3D co-culture model of human small intestinal organoids and MSCs, which allows to study the regenerative effects of MSCs on intestinal epithelium in a more physiologically relevant setting than existing in vitro systems. Using this model we mimicked chemotherapy-mediated damage of the intestinal epithelium. The treatment with busulfan, the chemotherapeutic commonly used as conditioning regiment before the HSCT, affected pathways regulating epithelial to mesenchymal transition, proliferation, and apoptosis in small intestinal organoids, as shown by transcriptomic and proteomic analysis. The co-culture of busulfan-treated intestinal organoids with MSCs reversed the effects of busulfan on the transcriptome and proteome of intestinal epithelium, which we also confirmed by functional evaluation of proliferation and apoptosis.
    CONCLUSIONS: Collectively, we demonstrate that our in vitro co-culture system is a new valuable tool to facilitate the investigation of the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestinal epithelium. This could benefit further optimization of the use of MSCs in HSCT patients.
    DOI:  https://doi.org/10.1186/s13287-024-03738-9
  12. J Exp Clin Cancer Res. 2024 May 02. 43(1): 132
    Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside.
    Luca Varinelli, Davide Battistessa, Marcello Guaglio, Susanna Zanutto, Oscar Illescas, Ewelina J Lorenc, Federica Pisati, Shigeki Kusamura, Laura Cattaneo, Giovanna Sabella, Massimo Milione, Alessia Perbellini, Sara Noci, Cinzia Paolino, Elisabetta Khun, Margherita Galassi, Tommaso Cavalleri, Marcello Deraco, Manuela Gariboldi, Dario Baratti.
       BACKGROUND: Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been reported to improve survival, but peritoneal recurrence rates are still high and there is no consensus on the drug of choice for HIPEC. The aim of this study was to use patient derived organoids (PDO) to build a relevant CRCPM model to improve HIPEC efficacy in a comprehensive bench-to-bedside strategy.
    METHODS: Oxaliplatin (L-OHP), cisplatin (CDDP), mitomycin-c (MMC) and doxorubicin (DOX) were used to mimic HIPEC on twelve PDO lines derived from twelve CRCPM patients, using clinically relevant concentrations. After chemotherapeutic interventions, cell viability was assessed with a luminescent assay, and the obtained dose-response curves were used to determine the half-maximal inhibitory concentrations. Also, induction of apoptosis by different HIPEC interventions on PDOs was studied by evaluating CASPASE3 cleavage.
    RESULTS: Response to drug treatments varied considerably among PDOs. The two schemes with better response at clinically relevant concentrations included MMC alone or combined with CDDP. L-OHP showed relative efficacy only when administered at low concentrations over a long perfusion period. PDOs showed that the short course/high dose L-OHP scheme did not appear to be an effective choice for HIPEC in CRCPM. HIPEC administered under hyperthermia conditions enhanced the effect of chemotherapy drugs against cancer cells, affecting PDO viability and apoptosis. Finally, PDO co-cultured with cancer-associated fibroblast impacted HIPEC treatments by increasing PDO viability and reducing CASPASES activity.
    CONCLUSIONS: Our study suggests that PDOs could be a reliable in vitro model to evaluate HIPEC schemes at individual-patient level and to develop more effective treatment strategies for CRCPM.
    Keywords:  Chemotherapy; Colorectal cancer; HIPEC; Organoids; Peritoneal metastases; Personalized medicine; Tailored therapies
    DOI:  https://doi.org/10.1186/s13046-024-03052-5
  13. Commun Med (Lond). 2024 May 03. 4(1): 79
    Independent transcriptional patterns reveal biological processes associated with disease-free survival in early colorectal cancer.
    Daan G Knapen, Sara Hone Lopez, Derk Jan A de Groot, Jacco-Juri de Haan, Elisabeth G E de Vries, Rodrigo Dienstmann, Steven de Jong, Arkajyoti Bhattacharya, Rudolf S N Fehrmann.
       BACKGROUND: Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or obscured by other processes' patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes.
    METHODS: In this study we (1) integrated transcriptomes (n = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results RESULTS: We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes.
    CONCLUSIONS: This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC.
    DOI:  https://doi.org/10.1038/s43856-024-00504-z
  14. Nat Commun. 2024 Apr 30. 15(1): 3653
    Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
    Bingjie Guan, Youdong Liu, Bowen Xie, Senlin Zhao, Abudushalamu Yalikun, Weiwei Chen, Menghua Zhou, Qi Gu, Dongwang Yan.
      Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.
    DOI:  https://doi.org/10.1038/s41467-024-48100-y
  15. Front Oncol. 2024 ;14 1365762
    Identification of differentially expressed genes and splicing events in early-onset colorectal cancer.
    Olivia M Marx, Marc M Mankarious, Walter A Koltun, Gregory S Yochum.
       Background: The incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, < 50 years old) patients versus later-onset colorectal cancer (LOCRC, > 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC.
    Methods: We performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients. The EOCRC and LOCRC cohorts were matched for demographic and clinical characteristics. We used The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database for validation. We used a series of computational and bioinformatic tools to identify EOCRC-specific differentially expressed genes, molecular pathways, predicted cell populations, differential gene splicing events, and predicted neoantigens.
    Results: We identified an eight-gene signature in EOCRC comprised of ALDOB, FBXL16, IL1RN, MSLN, RAC3, SLC38A11, WBSCR27 and WNT11, from which we developed a score predictive of overall CRC patient survival. On the entire set of genes identified in normal tissues and tumors, cell type deconvolution analysis predicted a differential abundance of immune and non-immune populations in EOCRC versus LOCRC. Gene set enrichment analysis identified increased expression of splicing machinery in EOCRC. We further found differences in alternative splicing (AS) events, including one within the long non-coding RNA, HOTAIRM1. Additional analysis of AS found seven events specific to EOCRC that encode potential neoantigens.
    Conclusion: Our transcriptome analyses identified genetic and molecular features specific to EOCRC which may inform future screening, development of prognostic indicators, and novel drug targets.
    Keywords:  colorectal cancer; early-onset; late-onset; splicing; transcriptome
    DOI:  https://doi.org/10.3389/fonc.2024.1365762
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