bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–05–26
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Dark force rising: Reawakening and targeting of fetal-like stem cells in colorectal cancer.
  2. A consensus molecular subtypes classification strategy for clinical colorectal cancer tissues.
  3. Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer.
  4. Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.
  5. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.
  6. Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy.
  7. The selective sponging of miRNAs by OIP5-AS1 regulates metabolic reprogramming of pyruvate in adenoma-carcinoma transition of human colorectal cancer.
  8. Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.
  9. Patterning and folding of intestinal villi by active mesenchymal dewetting.
  1. Cell Rep. 2024 May 23. pii: S2211-1247(24)00598-9. [Epub ahead of print]43(6): 114270
    Dark force rising: Reawakening and targeting of fetal-like stem cells in colorectal cancer.
    Sigrid K Fey, Nuria Vaquero-Siguero, Rene Jackstadt.
      Stem cells play pivotal roles in maintaining intestinal homeostasis, orchestrating regeneration, and in key steps of colorectal cancer (CRC) initiation and progression. Intriguingly, adult stem cells are reduced during many of these processes. On the contrary, primitive fetal programs, commonly detected in development, emerge during tissue repair, CRC metastasis, and therapy resistance. Recent findings indicate a dynamic continuum between adult and fetal stem cell programs. We discuss critical mechanisms facilitating the plasticity between stem cell states and highlight the heterogeneity observed upon the appearance of fetal-like states. We focus on therapeutic opportunities that arise by targeting fetal-like CRC cells and how those concepts can be translated into the clinic.
    Keywords:  CP: Cancer; CP: Stem cell research
    DOI:  https://doi.org/10.1016/j.celrep.2024.114270
  2. Life Sci Alliance. 2024 Aug;pii: e202402730. [Epub ahead of print]7(8):
    A consensus molecular subtypes classification strategy for clinical colorectal cancer tissues.
    Tim R de Back, Tan Wu, Pascale Jm Schafrat, Sanne Ten Hoorn, Miaomiao Tan, Lingli He, Sander R van Hooff, Jan Koster, Lisanne E Nijman, Geraldine R Vink, Inès J Beumer, Clara C Elbers, Kristiaan J Lenos, Dirkje W Sommeijer, Xin Wang, Louis Vermeulen.
      Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA. We evaluated the classification accuracy in two FFPE-RNA datasets with matched fresh-frozen (FF) RNA data, and an FF-derived RNA set. An FFPE-RNA application cohort of metastatic CRC patients was established, partly treated with anti-EGFR therapy. Key characteristics per CMS were assessed. Cross-referenced with matched benchmark FF CMS calls, the CMSFFPE classifier strongly improved classification accuracy in two FFPE datasets compared with the original CMSClassifier (63.6% versus 40.9% and 83.3% versus 66.7%, respectively). We recovered CMS-specific recurrence-free survival patterns (CMS4 versus CMS2: hazard ratio 1.75, 95% CI 1.24-2.46). Key molecular and clinical associations of the CMSs were confirmed. In particular, we demonstrated the predictive value of CMS2 and CMS3 for anti-EGFR therapy response (CMS2&3: odds ratio 5.48, 95% CI 1.10-27.27). The CMSFFPE classifier is an optimized FFPE-curated research tool for CMS classification of clinical CRC samples.
    DOI:  https://doi.org/10.26508/lsa.202402730
  3. Nat Commun. 2024 May 21. 15(1): 4342
    Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer.
    Jonas Langerud, Ina A Eilertsen, Seyed H Moosavi, Solveig M K Klokkerud, Henrik M Reims, Ingeborg F Backe, Merete Hektoen, Ole H Sjo, Marine Jeanmougin, Sabine Tejpar, Arild Nesbakken, Ragnhild A Lothe, Anita Sveen.
      Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.
    DOI:  https://doi.org/10.1038/s41467-024-48706-2
  4. Nat Commun. 2024 May 23. 15(1): 4393
    Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.
    Yuan Liang, Chao Luo, Lijun Sun, Tiange Feng, Wenzhen Yin, Yunhua Zhang, Michael W Mulholland, Weizhen Zhang, Yue Yin.
      Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.
    DOI:  https://doi.org/10.1038/s41467-024-48622-5
  5. Ann Oncol. 2024 May 03. pii: S0923-7534(24)00104-2. [Epub ahead of print]
    Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.
    M Ambrosini, B Rousseau, P Manca, O Artz, A Marabelle, T André, G Maddalena, G Mazzoli, R Intini, R Cohen, A Cercek, N H Segal, L Saltz, A M Varghese, R Yaeger, M Nusrat, Z Goldberg, G Y Ku, I El Dika, O Margalit, A Grinshpun, P Kasi, R Schilsky, A Lutfi, E Shacham-Shmueli, M Khan Afghan, L Weiss, C B Westphalen, V Conca, B Decker, G Randon, E Elez, M Fakih, A B Schrock, C Cremolini, P Jayachandran, M J Overman, S Lonardi, F Pietrantonio.
       BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.
    PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures.
    RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature.
    CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.
    Keywords:  POLD1 mutations; POLE mutations; immune checkpoint inhibitors; metastatic colorectal cancer; proofreading deficiency
    DOI:  https://doi.org/10.1016/j.annonc.2024.03.009
  6. Expert Opin Investig Drugs. 2024 May 22. 1-13
    Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy.
    Nadia Saoudi González, Paola Valeria Marchese, Iosune Baraibar, Javier Ros, Francesc Salvà, Marta Rodríguez, Clara Salvà, Caterina Vaghi, Adriana Alcaraz, Ariadna García, Josep Tabernero, Elena Élez.
       INTRODUCTION: The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time.
    AREAS COVERED: This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed.
    EXPERT OPINION: Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.
    Keywords:  Colorectal cancer; EGFR; HER2; epidermal growth factor; epidermal growth factor inhibitors; rechallenge
    DOI:  https://doi.org/10.1080/13543784.2024.2349287
  7. BMC Cancer. 2024 May 21. 24(1): 611
    The selective sponging of miRNAs by OIP5-AS1 regulates metabolic reprogramming of pyruvate in adenoma-carcinoma transition of human colorectal cancer.
    Jing-Yu Wang, Xiao-Ping Zhang, Hong-Kun Zhou, Hong-Xin Cai, Jin-Biao Xu, Bao-Gang Xie, Jean-Paul Thiery, Wu Zhou.
      RNA interactomes and their diversified functionalities have recently benefited from critical methodological advances leading to a paradigm shift from a conventional conception on the regulatory roles of RNA in pathogenesis. However, the dynamic RNA interactomes in adenoma-carcinoma sequence of human CRC remain unexplored. The coexistence of adenoma, cancer, and normal tissues in colorectal cancer (CRC) patients provides an appropriate model to address this issue. Here, we adopted an RNA in situ conformation sequencing technology for mapping RNA-RNA interactions in CRC patients. We observed large-scale paired RNA counts and identified some unique RNA complexes including multiple partners RNAs, single partner RNAs, non-overlapping single partner RNAs. We focused on the antisense RNA OIP5-AS1 and found that OIP5-AS1 could sponge different miRNA to regulate the production of metabolites including pyruvate, alanine and lactic acid. Our findings provide novel perspectives in CRC pathogenesis and suggest metabolic reprogramming of pyruvate for the early diagnosis and treatment of CRC.
    Keywords:  Adenoma-carcinoma transition; Colorectal carcinoma; Metabolic reprogramming; RNA interactomes
    DOI:  https://doi.org/10.1186/s12885-024-12367-7
  8. Cell Commun Signal. 2024 May 18. 22(1): 278
    Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.
    Qi Liu, Yajuan Zhang, Huimin Li, Hong Gao, Yijie Zhou, Dakui Luo, Zezhi Shan, Yufei Yang, Junyong Weng, Qingguo Li, Weiwei Yang, Xinxiang Li.
       BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood.
    METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses.
    RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy.
    CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.
    Keywords:  (S)-2,3-epoxysqualene; Chemoretherapy; Colorectal cancer; NF-κB pathway; Squalene epoxidase
    DOI:  https://doi.org/10.1186/s12964-024-01649-z
  9. Cell. 2024 May 20. pii: S0092-8674(24)00465-3. [Epub ahead of print]
    Patterning and folding of intestinal villi by active mesenchymal dewetting.
    Tyler R Huycke, Teemu J Häkkinen, Hikaru Miyazaki, Vasudha Srivastava, Emilie Barruet, Christopher S McGinnis, Ali Kalantari, Jake Cornwall-Scoones, Dedeepya Vaka, Qin Zhu, Hyunil Jo, Roger Oria, Valerie M Weaver, William F DeGrado, Matt Thomson, Krishna Garikipati, Dario Boffelli, Ophir D Klein, Zev J Gartner.
      Tissue folds are structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, finger-like protrusions that enable nutrient absorption. However, the molecular and mechanical processes driving villus morphogenesis remain unclear. Here, we identify an active mechanical mechanism that simultaneously patterns and folds the intestinal epithelium to initiate villus formation. At the cellular level, we find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. This symmetry-breaking process requires altered cell and extracellular matrix interactions that are enabled by matrix metalloproteinase-mediated tissue fluidization. Computational models, together with in vitro and in vivo experiments, revealed that these cellular features manifest at the tissue level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active dewetting of a thin liquid film.
    Keywords:  Cahn-Hilliard; active fluids; biophysics; cell adhesion; development; extracellular matrix; morphogenesis; patterning; phase separation; self-organization
    DOI:  https://doi.org/10.1016/j.cell.2024.04.039
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