bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–12–22
seven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Endosomal pH is an evolutionarily conserved driver of phenotypic plasticity in colorectal cancer.
  2. Dissecting the cellular reprogramming and tumor microenvironment in left- and right-sided Colorectal Cancer by single cell RNA sequencing.
  3. Longitudinal phosphoproteomics reveals the PI3K-PAK1 axis as a potential target for recurrent colorectal liver metastases.
  4. Bestrophin-4 relays HES4 and interacts with TWIST1 to suppress epithelial-to-mesenchymal transition in colorectal cancer cells.
  5. Deriving human intestinal organoids with functional tissue-resident macrophages all from pluripotent stem cells.
  6. USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer.
  7. Mini colons to study cancer ex vivo.
  1. NPJ Syst Biol Appl. 2024 Dec 19. 10(1): 149
    Endosomal pH is an evolutionarily conserved driver of phenotypic plasticity in colorectal cancer.
    Hari Prasad, Harshavardhan Bv, Ayalur Raghu Subbalakshmi, Susmita Mandal, Mohit Kumar Jolly, Sandhya S Visweswariah.
      Dysregulated pH is now recognised as a hallmark of cancer. Recent evidence has revealed that the endosomal pH regulator Na+/H+ exchanger NHE9 is upregulated in colorectal cancer to impose a pseudo-starvation state associated with invasion, highlighting an underexplored mechanistic link between adaptive endosomal reprogramming and malignant transformation. In this study, we use a model that quantitatively captures the dynamics of the core regulatory network governing epithelial mesenchymal plasticity. The model recapitulated NHE9-induced calcium signalling and the emergence of migratory phenotypes in colorectal cancer cells. Model predictions were compared with patient data and experimental results from RNA sequencing analysis of colorectal cancer cells with stable NHE9 expression. Mathematical analyses identified that tumours leverage elevated NHE9 levels to delay the transition of cells to a mesenchymal state and allow for metastatic progression. Ectopic expression of NHE9 is sufficient to induce loss of epithelial nature but does not fully couple with gain of mesenchymal state, resulting in a hybrid epithelial-mesenchymal population with increased aggressiveness and metastatic competence. Higher NHE9 expression is associated with cancer cell migration, and the effect appears to be independent of hypoxia status. Our data suggests that alterations in endosomal pH, an evolutionarily conserved starvation response, may be hijacked by colorectal cancer cells to drive phenotypic plasticity and invasion. We propose that cancer cells rewire their endosomal pH not only to meet the demands of rapid cell proliferation, but also to enable invasion, metastasis, and cell survival. Endosomal pH may be an attractive therapeutic target for halting tumour progression.
    DOI:  https://doi.org/10.1038/s41540-024-00463-0
  2. Transl Res. 2024 Dec 13. pii: S1931-5244(24)00198-1. [Epub ahead of print]276 22-37
    Dissecting the cellular reprogramming and tumor microenvironment in left- and right-sided Colorectal Cancer by single cell RNA sequencing.
    Congxue Hu, Xiaozhi Huang, Jing Chen, Weixin Liang, Kaiyue Yang, Hui Jiang, Kuan Yang, Qi Ou, Xia Li, Yunpeng Zhang.
      Sidedness and staging are major sources of tumor microenvironment (TME) differences in colorectal cancer (CRC). Subpopulation compositions of stromal cells and immune cells, and interactions between cells collectively constitute the immunosuppressive microenvironment of CRC. In this study, we comprehensively collected single-cell RNA sequencing data from public databases. We filtered out 126,279 cells from 55 CRC samples to characterize the differences in cellular composition, and to elucidate the transcriptional features and potential functions of cell types, temporally and positionally. We observed an increased degree of hypoxia in right side-specific cancer cells compared to left-sided cancer. Cancer-associated fibroblasts (CAFs) illustrated molecular signatures tremendously tended to be associated with functions that orchestrate extracellular matrix remodeling and angiogenesis, and right-sided CAFs characterized the stronger cancer invasion signals. Crosstalk between side-specific cancer cells and stromal together with immune cells characterized CRC via different sample groups, and was pertinent to worse prognosis. Our study captured immunosuppressive pattern exhibiting more intricate intercellular interactions in right-sided CRC. Additionally, during malignant progression of CRC, the transformation of CD8+ T cell cytotoxic and exhausted properties and macrophage pro-inflammatory and anti-inflammatory properties epitomized the cellular reprogramming phenomenon that the function of TME shifted from promoting immunity to suppressive immunity. Our study shed lights on refining personalized therapeutic regimens during malignant progression in left- and right-sided CRCs.
    Keywords:  Colorectal cancer; Sidedness; Single-cell RNA sequencing; Stage; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trsl.2024.12.002
  3. Cell Rep. 2024 Dec 11. pii: S2211-1247(24)01412-8. [Epub ahead of print] 115061
    Longitudinal phosphoproteomics reveals the PI3K-PAK1 axis as a potential target for recurrent colorectal liver metastases.
    Daigo Gunji, Yuichi Abe, Satoshi Muraoka, Ryohei Narumi, Junko Isoyama, Narumi Ikemoto, Mimiko Ishida, Akina Shinkura, Takeshi Tomonaga, Satoshi Nagayama, Yu Takahashi, Yosuke Fukunaga, Yoshiharu Sakai, Kazutaka Obama, Jun Adachi.
      The resistance of colorectal cancer liver metastases (CRLMs) to 5-fluorouracil (5-FU) chemotherapy remains a significant global health challenge. We investigated the phosphoproteomic dynamics of serial tissue sections obtained from initial metastases and recurrent tumors collected from 24 patients to address this unmet need for innovative therapeutic strategies for patients with CRLM with a poor prognosis. Our analysis revealed the activation of PAK kinase in patients with CRLM with a poor prognosis. Using an unbiased computational approach, we conducted a correlation analysis between PAK1 kinase activity and 545 drug sensitivity profiles across 35 colorectal cancer cell lines and identified PI3K inhibitors as potential therapeutic candidates. The efficacy of the FDA-approved PI3K inhibitor copanlisib was validated in 5-FU-resistant cell lines with high PAK1 kinase activity both in vitro and in vivo. This study presents an effective strategy for drug target discovery based on kinase activity, and the concept of this approach is widely applicable.
    Keywords:  CP: Cancer; chemotherapy resistance; colorectal cancer liver metastases; computational approaches; drug repositioning; phosphoproteomic dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115061
  4. Elife. 2024 Dec 19. pii: RP88879. [Epub ahead of print]12
    Bestrophin-4 relays HES4 and interacts with TWIST1 to suppress epithelial-to-mesenchymal transition in colorectal cancer cells.
    Zijing Wang, Bihan Xia, Shaochong Qi, Xian Zhang, Xiaoshuang Zhang, Yan Li, Huimin Wang, Miao Zhang, Ziyi Zhao, David Kerr, Li Yang, Shijie Cai, Jilin Yang.
      Bestrophin isoform 4 (BEST4) is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of BEST4+ mature colonocytes in humans. However, if the role of BEST4 is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that BEST4 overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumour growth and the liver metastasis in vivo. BEST4 is co-expressed with hairy/enhancer of split 4 (HES4) in the nucleus of cells, and HES4 signals BEST4 by interacting with the upstream region of the BEST4 promoter. BEST4 is epistatic to HES4 and downregulates TWIST1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumour growth and induces EMT. Furthermore, the low level of the BEST4 mRNA is correlated with advanced and the worse prognosis, suggesting its potential role involving CRC progression.
    Keywords:  TWIST1; bestrophin-4; cancer biology; cell biology; colorectal cancer; epithelial-mesenchymal transition; hairy/enhancer of split 4; human
    DOI:  https://doi.org/10.7554/eLife.88879
  5. Cell Mol Gastroenterol Hepatol. 2024 Dec 17. pii: S2352-345X(24)00199-1. [Epub ahead of print] 101444
    Deriving human intestinal organoids with functional tissue-resident macrophages all from pluripotent stem cells.
    Kentaro Tominaga, Daniel O Kechele, J Guillermo Sanchez, Simon Vales, Ingrid Jurickova, Lizza Roman, Akihiro Asai, Jacob R Enriquez, Heather A McCauley, Keishi Kishimoto, Kentaro Iwasawa, Akaljot Singh, Yuko Horio, Jorge O Múnera, Takanori Takebe, Aaron M Zorn, Michael A Helmrath, Lee A Denson, James M Wells.
       BACKGROUND & AIMS: Organs of the gastrointestinal tract contain tissue-resident immune cells that function during tissue development, homeostasis, and disease. However, most published human organoid model systems lack resident immune cells, thus limiting their potential as disease avatars. For example, human intestinal organoids (HIOs) derived from pluripotent stem cells contain epithelial and various mesenchymal cell types but lack immune cells. In this study, we aimed to develop an HIO model with functional tissue-resident macrophages.
    METHODS: HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro. Following two weeks of co-culture, the organoids were used for transcriptional profiling, functional analysis of macrophages, or transplanted into immunocompromised mice and matured in vivo for an additional 10-12 weeks.
    RESULTS: Macrophages were incorporated into developing HIOs and persisted for 2 weeks in vitro HIOs and for at least 12 weeks in HIOs in vivo. These co-cultured macrophages had a transcriptional signature that resembled those in the human fetal intestine, indicating that they were acquiring the features of tissue-resident macrophages. HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals such as lipopolysaccharide, which could be reversed with IL-10.
    CONCLUSIONS: We generated an HIO system containing functional tissue-resident macrophages for an extended period. This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease.
    Keywords:  human intestinal organoids; immune cells; inflammatory bowel disease; tissue-resident macrophages
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.101444
  6. Cell Death Discov. 2024 Dec 18. 10(1): 492
    USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer.
    Ji Hye Shin, Mi-Jeong Kim, Ji Young Kim, Bongkum Choi, Yeeun Kang, Seo Hyun Kim, Ha-Jeong Lee, Dohee Kwon, Yong Beom Cho, Kyeong Kyu Kim, Eunyoung Chun, Ki-Young Lee.
      The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF.
    DOI:  https://doi.org/10.1038/s41420-024-02255-1
  7. Nat Cancer. 2024 Dec 17.
    Mini colons to study cancer ex vivo.
    Ioanna Pavlaki.
      
    DOI:  https://doi.org/10.1038/s43018-024-00832-y
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