bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021–09–05
twelve papers selected by
Maria-Virginia Giolito, IRFAC/UMR-S1113 INSERM
  1. Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression.
  2. Inflation comes before the fall: How epithelial stretch drives crypt fission.
  3. Tumor Vascular Microenvironment of Colorectal Hepatic Metastasis and Chemotherapy Response.
  4. A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer.
  5. Current status and future perspective of immune checkpoint inhibitors in colorectal cancer.
  6. Jagged-1 Expression Level Is Correlated With Recurrence of Stage III Colorectal Cancer in Patients Receiving Adjuvant Chemotherapy.
  7. High-Fat Diet Promotes Colorectal Tumorigenesis through Modulating Gut Microbiota and Metabolites.
  8. The tight junction protein ZO-1 is dispensable for barrier function but critical for effective mucosal repair.
  9. Deoxycholic acid delays the wound healing of colonic epithelial cells via transmembrane G-protein-coupled receptor 5.
  10. Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
  11. Organ-on-chip approaches for intestinal 3D in vitro modelling.
  12. The Landmark Discovery That Paved the Way to a Mechanistic Understanding of P53 Gain of Function and Personalized Medicine.
  1. Cell Rep Med. 2021 Aug 17. 2(8): 100353
    Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression.
    Jingjing Qi, Adeline Crinier, Bertrand Escalière, Youqiong Ye, Zhengting Wang, Tianyu Zhang, Luciana Batista, Hongzhi Liu, Liwen Hong, Ningbo Wu, Mingnan Zhang, Lei Chen, Yingbin Liu, Lei Shen, Emilie Narni-Mancinelli, Eric Vivier, Bing Su.
      Innate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1+ ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC.
    Keywords:  ILC heterogeneity; ILC1s; ILC2s; SLAMF1; TIGIT; biomarker; blood; colrectal cancer; inate lymphoid cells; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100353
  2. Cell Stem Cell. 2021 Sep 02. pii: S1934-5909(21)00345-3. [Epub ahead of print]28(9): 1505-1506
    Inflation comes before the fall: How epithelial stretch drives crypt fission.
    Geraldine M Jowett, Eileen Gentleman.
      In this issue of Cell Stem Cell, Tallapragada et al. (2021) present an intestinal organoid culture system for high-throughput live imaging to investigate niche-independent mechanisms of crypt fission. They find that Piezo activity downregulates Lgr5 expression in stretched epithelial cells within inflated organoids, which form multiple new crypts upon collapse.
    DOI:  https://doi.org/10.1016/j.stem.2021.08.008
  3. Anticancer Res. 2021 Sep;41(9): 4505-4513
    Tumor Vascular Microenvironment of Colorectal Hepatic Metastasis and Chemotherapy Response.
    Hirotaka Okamoto, Shugo Shiba, Hiroshi Iino, Makoto Sudoh, Daisuke Ichikawa.
       BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)].
    PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined.
    RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly.
    CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.
    Keywords:  Metastatic hepatic tumor; angiogenesis; chemotherapy response; colorectal cancer; ring enhancement on CT; tumor vascular microenvironment
    DOI:  https://doi.org/10.21873/anticanres.15261
  4. Cell Oncol (Dordr). 2021 Aug 30.
    A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer.
    Alexandros Georgiou, Adam Stewart, Georgios Vlachogiannis, Lisa Pickard, Nicola Valeri, David Cunningham, Steven R Whittaker, Udai Banerji.
       PURPOSE: We hypothesised that plasticity in signal transduction may be a mechanism of drug resistance and tested this hypothesis in the setting of cetuximab resistance in patients with KRAS/NRAS/BRAFV600 wild-type colorectal cancer (CRC).
    METHODS: A multiplex antibody-based platform was used to study simultaneous changes in signal transduction of 55 phospho-proteins in 12 KRAS/NRAS/BRAFV600 wild-type CRC cell lines (6 cetuximab sensitive versus 6 cetuximab resistant) following 1 and 4 h in vitro cetuximab exposure. We validated our results in CRC patient samples (n = 4) using ex vivo exposure to cetuximab in KRAS/NRAS/BRAFV600 cells that were immunomagnetically separated from the serous effusions of patients with known cetuximab resistance.
    RESULTS: Differences in levels of phospho-proteins in cetuximab sensitive and resistant cell lines included reductions in phospho-RPS6 and phospho-PRAS40 in cetuximab sensitive, but not cetuximab resistant cell lines at 1 and 4 h, respectively. In addition, phospho-AKT levels were found to be elevated in 3/4 patient samples following ex vivo incubation with cetuximab for 1 h. We further explored these findings by studying the effects of combinations of cetuximab and two PI3K pathway inhibitors in 3 cetuximab resistant cell lines. The addition of PI3K pathway inhibitors to cetuximab led to a significantly higher reduction in colony formation capacity compared to cetuximab alone.
    CONCLUSION: Our findings suggest activation of the PI3K pathway as a mechanism of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type CRC.
    Keywords:  Cetuximab; Colorectal cancer; Phospho-proteomics; Proteomics; Resistance mechanisms; Signalling adaptations
    DOI:  https://doi.org/10.1007/s13402-021-00628-7
  5. Cancer Lett. 2021 Aug 28. pii: S0304-3835(21)00350-5. [Epub ahead of print]521 119-129
    Current status and future perspective of immune checkpoint inhibitors in colorectal cancer.
    Cong Zhou, Xiaojiao Cheng, Shuiping Tu.
      Immune checkpoint inhibitors (ICIs), as a subverter of immunotherapy in oncology, are changing all aspects of therapy for malignant tumors, especially their remarkable effects on melanoma and non-small cell lung cancer (NSCLC). For colorectal cancer (CRC), only a small number of patients with high immunogenicity (microsatellite instability-high/mismatch-repair deficient (MSI-H/dMMR)) benefit greatly from ICIs treatment, and most CRC patients with low immunogenicity (microsatellite instability-low/mismatch-repair proficient (MSI-L/pMMR)) do not. Currently, numerous clinical trials are ongoing to improve CRC patients' response to ICIs immunotherapy through better patient selection and novel combination strategies. Thus, this review discusses the current status and latest progress of ICIs treatment in CRC. We expect that these studies can change the pattern of CRC immunotherapy in the future.
    Keywords:  Colorectal cancer; Immune checkpoint inhibitor; Immunotherapy
    DOI:  https://doi.org/10.1016/j.canlet.2021.07.023
  6. Anticancer Res. 2021 Sep;41(9): 4645-4650
    Jagged-1 Expression Level Is Correlated With Recurrence of Stage III Colorectal Cancer in Patients Receiving Adjuvant Chemotherapy.
    Hong-Beum Kim, Seul-Bi Lee, Seong-Jung Kim, Hee-Jeong Lee, Sang-Gon Park.
       BACKGROUND/AIM: Previous reports have indicated that increased expression of Jagged-1 (JAG1) may predict chemotherapy response and poor prognosis for patients with recurrent or metastatic colorectal cancer (CRC). This study aimed to investigate the clinical impact of JAG1 expression level in patients with CRC, including recurrence, especially in those diagnosed with lymph node-positive stage III CRC who underwent complete resection and appropriate adjuvant chemotherapy.
    PATIENTS AND METHODS: All patients were enrolled through a retrospective chart review, and only those for whom the clinical course and all clinical information were adequately determined according to the inclusion criteria were selected for retrospective review through medical records. Immunohistochemical staining of JAG1 was performed using paraffin-embedded tissue. JAG1 expression was determined by scoring for staining intensity and percentage of positively stained cells; the final JAG1 score was determined as the sum of both scores.
    RESULTS: Sixteen patients who experienced relapse and 15 without (for over 3 years) were selected. The protein expression level of JAG1 showed a tendency for being lower in the group without recurrence, although not statistically significantly (p=0.083); however, the mean JAG1 expression score was significantly lower in the group without recurrence (1.53 vs. 3.19; p=0.004). The patients were divided into two groups with low and high JAG1 expression. The results showed that high JAG1 expression was significantly associated with recurrence of stage III CRC (p=0.029).
    CONCLUSION: The expression of JAG1 may be a potential novel biomarker for predicting CRC recurrence.
    Keywords:  JAG1; Jagged-1; adjuvant chemotherapy; biomarker; colorectal cancer recurrence; lymph node-positive stage III CRC
    DOI:  https://doi.org/10.21873/anticanres.15278
  7. Gastroenterology. 2021 Aug 27. pii: S0016-5085(21)03439-9. [Epub ahead of print]
    High-Fat Diet Promotes Colorectal Tumorigenesis through Modulating Gut Microbiota and Metabolites.
    Jia Yang, Hong Wei, Yunfei Zhou, Chun-Ho Szeto, Chuangen Li, Yufeng Lin, Olabisi O Coker, Harry Cheuk Hay Lau, Anthony Wh Chan, Joseph Jy Sung, Jun Yu.
       BACKGROUND & AIMS: Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites.
    METHODS: HFD or control diet (CD) was fed to mice littermates in CRC mouse models of azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were utilized for validation. Gut microbiota and metabolites were respectively detected by metagenomic sequencing and high-performance liquid chromatography-mass spectrometry. Gut barrier function was determined by lipopolysaccharides (LPS) level and transmission electron microscopy.
    RESULTS: HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with CD-fed mice. Gut microbiota depletion by antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipes sp. Marseille-P5997 and Alistipes sp. 5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration including elevated lysophosphatidic acid (LPA) which was confirmed to promote CRC cell proliferation and impair cell junction was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function and induced oncogenic genes expression.
    CONCLUSION: HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated LPA, and gut barrier dysfunction in mice.
    Keywords:  Colon Cancer; Dietary nutrient; Gut Products; Microbiome
    DOI:  https://doi.org/10.1053/j.gastro.2021.08.041
  8. Gastroenterology. 2021 Aug 31. pii: S0016-5085(21)03465-X. [Epub ahead of print]
    The tight junction protein ZO-1 is dispensable for barrier function but critical for effective mucosal repair.
    Wei-Ting Kuo, Li Zuo, Matthew A Odenwald, Shariq Madha, Gurminder Singh, Christine B Gurniak, Clara Abraham, Jerrold R Turner.
       BACKGROUND: S AND AIMS: Increased permeability is implicated in the pathogenesis of intestinal disease. In vitro and in vivo studies have linked downregulation of the scaffolding protein ZO-1, encoded by the TJP1 gene, to increased tight junction permeability. This has not, however, been tested in vivo. Here, we assessed the contributions of ZO-1 to epithelial barrier function and mucosal homeostasis.
    METHODS: Public GEO data sets and biopsies from inflammatory bowel disease (IBD) patients and healthy controls were analyzed. Tjp1f/f; vil-CreTg mice with intestinal epithelial-specific ZO-1 knockout (ZO-1KO.IEC) mice and Tjp1f/f mice littermates, without Cre expression, were studied using chemical and immune-mediated models of disease as well as colonic stem cell cultures.
    RESULTS: ZO-1 transcript and protein expression were reduced in IBD patient biopsies. Despite mildly increased intestinal permeability, ZO-1KO.IEC mice were healthy and did not develop spontaneous disease. ZO-1KO.IEC mice were hypersensitive to mucosal insults and displayed defective repair. Further, ZO-1-deficient colonic epithelia failed to upregulate proliferation in response to damage in vivo or Wnt signaling in vitro. ZO-1 associated with centrioles in interphase cells and mitotic spindle poles during division. In the absence of ZO-1, mitotic spindles failed to correctly orient, resulting in mitotic catastrophe and abortive proliferation. ZO-1 is, therefore, critical for upregulation of epithelial proliferation and successful completion of mitosis.
    CONCLUSION: ZO-1 makes critical, tight junction-independent contributions to Wnt signaling and mitotic spindle orientation. As a result, ZO-1 is essential for mucosal repair. We speculate that ZO-1 downregulation may be one cause of ineffective mucosal healing in IBD patients.
    Keywords:  Wnt; inflammatory bowel disease; intestinal permeability; mitosis; mitotic spindle
    DOI:  https://doi.org/10.1053/j.gastro.2021.08.047
  9. J Gastroenterol Hepatol. 2021 Sep 03.
    Deoxycholic acid delays the wound healing of colonic epithelial cells via transmembrane G-protein-coupled receptor 5.
    Yuka Azuma, Kazuhiko Uchiyama, Takeshi Sugaya, Takeshi Yasuda, Hikaru Hashimoto, Mariko Kajiwara, Satoshi Sugino, Hiroaki Kitae, Takashi Torii, Katsura Mizushima, Toshifumi Doi, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiro Kamada, Takeshi Ishikawa, Tomohisa Takagi, Yuji Naito, Yoshito Itoh.
       BACKGROUND AND AIM: Efficient intestinal wound healing is essential for good prognoses of ulcerative colitis (UC). Although bile acids and the transmembrane G-protein-coupled receptor (TGR) 5 have been reported to affect wound healing in intestinal epithelial cells, the detailed underlying mechanisms are unclear. Here, we investigated the role of TGR5 in wound healing in the context of colonic epithelial cells in the presence of bile acids.
    METHODS: The expression of TGR5 in the colonic epithelium of both a dextran sulfate sodium (DSS)-induced colitis mouse model (recovery phase), and UC patients in clinical remission, was evaluated. Young adult mouse colonic epithelial (YAMC) cells were then used to evaluate wound healing after treatment with deoxycholic acid (DCA); TGR5 was silenced in YAMC cells via shRNA-transfection, and a wound-healing assay in the presence of DCA was performed. Furthermore, we investigated the role of the activation of AKT in the context of wound healing.
    RESULTS: The expression of TGR5 was decreased in the colonic epithelium of both mice with DSS-induced colitis and UC patients. Additionally, DCA significantly delayed wound healing in YAMC cells but not in TGR5 silenced ones. Of note, the DCA-induced activation of AKT signaling in YAMC cells was inhibited by TGR5 silencing, and AKT inhibitors prevented the wound healing delay induced by DCA.
    CONCLUSIONS: Overall, we show that DCA delays wound healing in the context of colonic epithelial cells through AKT activation. These results may support the development of new therapeutic approaches for epithelial regeneration in UC.
    Keywords:  bile acids; deoxycholic acid; transmembrane G-protein-coupled receptor; ulcerative colitis; wound healing
    DOI:  https://doi.org/10.1111/jgh.15676
  10. Cancer Discov. 2021 Sep 03. pii: candisc.0003.2021. [Epub ahead of print]
    Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
    Fernanda G Herrera, Catherine Ronet, Maria Ochoa de Olza, David Barras, Isaac Crespo, Massimo Andreatta, Jesus Corria-Osorio, Aodrenn Spill, Fabrizio Benedetti, Raphael Genolet, Angela Orcurto, Martina Imbimbo, Eleonora Ghisoni, Blanca Navarro Rodrigo, Dominik R Berthold, Apostolos Sarivalasis, Khalil Zaman, Rafael Duran, Clarisse Dromain, John Prior, Niklaus Schaefer, Jean Bourhis, Georgia Dimopoulou, Zoi Tsourti, Marius Messemaker, Thomas Smith, Sarah E Warren, Periklis Foukas, Sylvie Rusakiewicz, Mikael J Pittet, Stefan Zimmermann, Christine Sempoux, Urania Dafni, Alexandre Harari, Lana E Kandalaft, Santiago J Carmona, Denarda Dangaj Laniti, Melita Irving, George Coukos.
      Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand Rae1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide and immune checkpoint blockade to patients with immune desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low-T cell infiltrated tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0003
  11. Cell Mol Gastroenterol Hepatol. 2021 Aug 25. pii: S2352-345X(21)00182-X. [Epub ahead of print]
    Organ-on-chip approaches for intestinal 3D in vitro modelling.
    Joana Pimenta, Ricardo Ribeiro, Raquel Almeida, Pedro F Costa, Marta A da Silva, Bruno Pereira.
      The intestinal epithelium has one of the highest turnover rates in the human body, which is supported by intestinal stem cells. Culture models of intestinal physiology have been evolving to incorporate different tissue and microenvironmental elements. However, these models also display gaps that limit their similarity with native conditions. Microfluidics technology arose from the application of microfabrication techniques to fluid manipulation. Recently, microfluidic approaches have been coupled with cell culture, creating self-contained and modular in vitro models with easily controllable features named organs-on-chip. Intestine-on-chip models have enabled the recreation of the proliferative and differentiated compartments of the intestinal epithelium, the long-term maintenance of commensals and the intraluminal perfusion of organoids. Plus, studies based on human primary intestinal cells revealed that these systems have a closer transcriptomic profile and functionality to the intestine in vivo, when compared with other in vitro models. The design flexibility inherent to microfluidic technology allows the simultaneous combination of components such as shear stress, peristalsis-like strain, 3D structure, oxygen gradient and co-cultures with other important cell types involved in gut physiology. The versatility and complexity of the intestine-on-chip grants it the potential for applications in disease modelling, host-microbiota studies, stem cell biology, and, ultimately, the translation to the pharmaceutical industry and clinics, as a reliable high-throughput platform for drug testing and personalized medicine, respectively. This review focuses on the physiological importance of several components that have been incorporated into intestine-on-chip models and highlights interesting features developed in other types of in vitro models that might contribute to the refinement of these systems.
    Keywords:  Intestinal stem cells; Intestine-on-chip; Microfabrication; Organoids
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.08.015
  12. Cancer Res. 2021 Sep 01. 81(17): 4394-4396
    The Landmark Discovery That Paved the Way to a Mechanistic Understanding of P53 Gain of Function and Personalized Medicine.
    Marco Napoli, Avani A Deshpande, Elsa R Flores.
      In 1990, Baker and colleagues reported their seminal findings in Cancer Research focusing on the transition from adenoma to carcinoma of the colon. By sequencing the TP53 locus in 58 colorectal tumors (25 adenomas and 33 carcinomas) and measuring its allelic deletions, they discovered that this transition requires the loss of one TP53 allele and the mutation of the other one. Here, we discuss how this landmark discovery shed a new light on p53 mutations, prompting the generation of novel mouse models that definitively proved the mutant p53 gain-of-function hypothesis suggested by these results. Finally, we evaluate the implications that the Vogelstein model of cancer progression had on numerous aspects of cancer biology and cancer care, including the characterization of tumor evolution and the response to therapy, and how it ultimately contributed to the wider adoption of early detection screenings and personalized medicine.See related article by Baker and colleagues, Cancer Res 1990;50:7717-22.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2382
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