bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–08–06
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype.
  2. Colonic stem cells from normal tissues adjacent to tumor drive inflammation and fibrosis in colorectal cancer.
  3. Cancer cell plasticity during tumor progression, metastasis and response to therapy.
  4. Cancer Stem Cells Persist Despite Cellular Damage, Emergence of the Refractory Cell Population.
  5. Colorectal cancer and therapy response: a focus on the main mechanisms involved.
  6. Loss of Pkd1 limits susceptibility to colitis and colorectal cancer.
  7. Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration.
  8. Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.
  9. Ceramides increase fatty acid utilization in intestinal progenitors to enhance stemness and increase tumor risk.
  1. Cell Rep. 2023 Aug 01. pii: S2211-1247(23)00938-5. [Epub ahead of print]42(8): 112927
    DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype.
    Estefania Cuesta-Borràs, Cándida Salvans, Oriol Arqués, Irene Chicote, Lorena Ramírez, Laia Cabellos, Jordi Martínez-Quintanilla, Alex Mur-Espinosa, Alejandro García-Álvarez, Jorge Hernando, Juan Ramón Tejedor, Oriol Mirallas, Elena Élez, Mario F Fraga, Josep Tabernero, Paolo Nuciforo, Jaume Capdevila, Héctor G Palmer, Isabel Puig.
      Tumor relapse is linked to rapid chemoresistance and represents a bottleneck for cancer therapy success. Engagement of a reduced proliferation state is a non-mutational mechanism exploited by cancer cells to bypass therapy-induced cell death. Through combining functional pulse-chase experiments in engineered cells and transcriptomic analyses, we identify DPPA3 as a master regulator of slow-cycling and chemoresistant phenotype in colorectal cancer (CRC). We find a vicious DPPA3-HIF1α feedback loop that downregulates FOXM1 expression via DNA methylation, thereby delaying cell-cycle progression. Moreover, downregulation of HIF1α partially restores a chemosensitive proliferative phenotype in DPPA3-overexpressing cancer cells. In cohorts of CRC patient samples, DPPA3 overexpression acts as a predictive biomarker of chemotherapeutic resistance that subsequently requires reduction in its expression to allow metastatic outgrowth. Our work demonstrates that slow-cycling cancer cells exploit a DPPA3/HIF1α axis to support tumor persistence under therapeutic stress and provides insights on the molecular regulation of disease progression.
    Keywords:  3D organoids; CP: Cancer; DNA methylation; FOXM1; cancer persistence; drug-tolerant persister cancer cell; hypoxia; recurrence; relapse; slow-cycling cancer cell; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2023.112927
  2. Cell Commun Signal. 2023 08 01. 21(1): 186
    Colonic stem cells from normal tissues adjacent to tumor drive inflammation and fibrosis in colorectal cancer.
    Yuanyuan Zhao, Mengmeng Guo, Fuqiang Zhao, Qian Liu, Xia Wang.
       BACKGROUND: In colorectal cancer (CRC), the normal tissue adjacent to tumor (NAT) communicates actively with the tumor. Adult stem cells from the colon play a crucial role in the development of the colonic epithelium. In the tumor microenvironment, however, it is unclear what changes have occurred in colonic stem cells derived from NAT.
    METHODS: Using an intestinal stem cell culture system, we cultured colonic cells from NAT and paired CRC tissue, as well as cells from healthy tissue (HLT). Clonogenicity and differentiation ability were used to compare the function of clones from NAT, HLT and CRC tissues. RNA high-throughput sequencing of these clones was used to identify the molecular characteristics of NAT-derived clones. Coculture of clones from HLT and CRC was used to assess molecular changes.
    RESULTS: We found that the morphological characteristics, clonogenic ability, and differentiation ability of NAT-derived clones were consistent with those of HLT-derived clones. However, NAT-derived clones changed at the molecular level. A number of genes were specifically activated in NAT. NAT-derived clones enriched pathways related to inflammation and fibrosis, including epithelial mesenchymal transition (EMT) pathway and TGF-beta signaling pathway. Our results also confirmed that NAT-derived clones could recruit fibroblasts in mice. In addition, HLT-derived clones showed high expression of FOSB when cocultured with tumor cells.
    CONCLUSIONS: Our results demonstrate that colonic stem cells from NAT in the tumor microenvironment undergo changes at the molecular level, and these molecular characteristics can be maintained in vitro, which can induce fibrosis and an inflammatory response. Video Abstract.
    Keywords:  Colorectal cancer; Fibrosis; Inflammation; Microenvironment; Stem cells
    DOI:  https://doi.org/10.1186/s12964-023-01140-1
  3. Nat Cancer. 2023 Aug 03.
    Cancer cell plasticity during tumor progression, metastasis and response to therapy.
    Andrea Pérez-González, Kevin Bévant, Cédric Blanpain.
      Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
    DOI:  https://doi.org/10.1038/s43018-023-00595-y
  4. Ann Surg Oncol. 2023 Jul 31.
    Cancer Stem Cells Persist Despite Cellular Damage, Emergence of the Refractory Cell Population.
    Ayumi Nagae, Norikatsu Miyoshi, Shiki Fujino, Masafumi Horie, Shinichi Yachida, Masaru Sasaki, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi.
       PURPOSE: Cancer stem cells (CSCs) are responsible for chemotherapy resistance and have unique properties that protect them from chemotherapy. Investigating CSCs may help to identify the population that is more resistant to treatments, leading to recurrence. We evaluated persisting CSCs, emerging after chemotherapy that cause tumor recurrence.
    METHODS: Using human colorectal cancer organoids prepared from surgical specimens, we looked at changes in CSCs, the emergence and changes in the original population, which single-cell analysis identified.
    RESULTS: With regards to changes in cancer stem cell markers, CD44 showed low levels after 5-fluorouracil administration. Once the CD44-ve population was sorted and cultured, the CD44+ve population gradually emerged, and the CD44-ve population decreased. Compared with the CD44-ve population of an organoid parent, the CD44-ve population proliferated after chemotherapeutic agent stimulation. The CD44-ve population was derived from the CD44+ve population before chemotherapeutic agents. In addition, when the CD44 variants were evaluated, the CD44v9 population remained. In single-cell analysis, we found that POU5F1 was highly expressed in the CD44low population. Velocity analysis showed that the CD44-ve population was induced after chemotherapy and expressed POU5F1. POU5F1-EGFP-Casp9 transfected organoids resulted in the appearance of a CD44-ve population after administration of a chemotherapeutic reagent. Both in vivo and in vitro, the dimerizer administration inhibited tumor growth significantly.
    CONCLUSIONS: POU5F1 is involved in chemotherapy resistance in relation to stemness. For the treatment against refractory tumors, such as the recurrence after chemotherapy, the treatment should target the emerging specific population such as CD44 (or CD44v9) and proliferative cancer cells.
    Keywords:  Anticancer treatment; Cancer stem cells; Colorectal cancer; Organoids; Xenograft model
    DOI:  https://doi.org/10.1245/s10434-023-13849-x
  5. Front Oncol. 2023 ;13 1208140
    Colorectal cancer and therapy response: a focus on the main mechanisms involved.
    Sara Tirendi, Barbara Marengo, Cinzia Domenicotti, Anna M Bassi, Vanessa Almonti, Stefania Vernazza.
       Introduction: The latest GLOBOCAN 2021 reports that colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Most CRC cases are sporadic and associated with several risk factors, including lifestyle habits, gut dysbiosis, chronic inflammation, and oxidative stress.
    Aim: To summarize the biology of CRC and discuss current therapeutic interventions designed to counteract CRC development and to overcome chemoresistance.
    Methods: Literature searches were conducted using PubMed and focusing the attention on the keywords such as "Current treatment of CRC" or "chemoresistance and CRC" or "oxidative stress and CRC" or "novel drug delivery approaches in cancer" or "immunotherapy in CRC" or "gut microbiota in CRC" or "systematic review and meta-analysis of randomized controlled trials" or "CSCs and CRC". The citations included in the search ranged from September 1988 to December 2022. An additional search was carried out using the clinical trial database.
    Results: Rounds of adjuvant therapies, including radiotherapy, chemotherapy, and immunotherapy are commonly planned to reduce cancer recurrence after surgery (stage II and stage III CRC patients) and to improve overall survival (stage IV). 5-fluorouracil-based chemotherapy in combination with other cytotoxic drugs, is the mainstay to treat CRC. However, the onset of the inherent or acquired resistance and the presence of chemoresistant cancer stem cells drastically reduce the efficacy. On the other hand, the genetic-molecular heterogeneity of CRC often precludes also the efficacy of new therapeutic approaches such as immunotherapies. Therefore, the CRC complexity made of natural or acquired multidrug resistance has made it necessary the search for new druggable targets and new delivery systems.
    Conclusion: Further knowledge of the underlying CRC mechanisms and a comprehensive overview of current therapeutic opportunities can provide the basis for identifying pharmacological and biological barriers that render therapies ineffective and for identifying new potential biomarkers and therapeutic targets for advanced and aggressive CRC.
    Keywords:  CRC; CSCs; adjuvant treatments; chemoresistance; drug delivery system
    DOI:  https://doi.org/10.3389/fonc.2023.1208140
  6. Oncogenesis. 2023 Aug 05. 12(1): 40
    Loss of Pkd1 limits susceptibility to colitis and colorectal cancer.
    Anna S Nikonova, Alexander Y Deneka, Flaviane N Silva, Shabnam Pirestani, Rossella Tricarico, Anna A Kiseleva, Yan Zhou, Emmanuelle Nicolas, Douglas B Flieder, Sergei I Grivennikov, Erica A Golemis.
      Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1-/-;Apc-/- organoids was reduced relative to Apc-/- organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.
    DOI:  https://doi.org/10.1038/s41389-023-00486-y
  7. J Transl Med. 2023 08 03. 21(1): 522
    Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration.
    Jean Bastin, Marine Sroussi, Ivan Nemazanyy, Pierre Laurent-Puig, Sophie Mouillet-Richard, Fatima Djouadi.
       BACKGROUND: Colorectal cancer (CRC) can be classified into four molecular subtypes (CMS) among which CMS1 is associated with the best prognosis, while CMS4, the mesenchymal subtype, has the worst outcome. Although mitochondria are considered to be hubs of numerous signaling pathways, the study of mitochondrial metabolism has been neglected for many years. Mitochondrial Complex I (CI) plays a dual role, both in energy and reactive oxygen species (ROS) production. However, the possible contribution of CI to tumorigenesis in cancer remains unclear. The purpose of this study was to investigate the CI under the prism of the CMS classification of CRC in ex vivo models.
    METHODS: Biochemical dosages, bioenergetics analysis and western-blot were used to characterize CI expression, function and redox balance in LoVo and MDST8 cell lines, belonging to CMS1 and CMS4 subgroups, respectively. Cell proliferation and migration were assessed by xCELLigence technology. Overproduction or scavenging of mitochondrial ROS (mtROS) were performed to analyze the effect of mtROS on proliferation, migration, and mesenchymal markers. Focal adhesion kinase (FAK) and its activation were analyzed by immunofluorescence. We assessed the distribution of two CI scores in CRC cohorts according to CMS classification and their relevance for patient survival.
    RESULTS: We found that CI is downregulated in CMS4 cells and is associated with elevated mtROS. We establish for the first time that in these migrating cells, mtROS production is maintained at optimal levels not only through changes in CI activity but also by inactivation/acetylation of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. We show that promoting or scavenging mtROS both mitigate CMS4 cells' migration. Our results also point to a mtROS-mediated focal adhesion kinase (FAK) activation, which likely sustains their migratory phenotype. Using cohorts of CRC patients, we document that the expression of CI is downregulated in the CMS4 subgroup, and that low CI expression is associated with poor prognosis. Patients' datasets reveal an inverse correlation between CI and the epithelial-mesenchymal transition (EMT) pathway.
    CONCLUSION: We showed that inhibition of CI contributes to heighten mtROS, which likely foster MDST8 migration and might account for the specific EMT signature of CMS4 tumors. These data reveal a novel role of mitochondrial CI in CRC, with biological consequences that may be targeted with anti- or pro-oxidant drugs in clinical practice.
    Keywords:  Colorectal cancer; Complex I; Consensus Molecular Subtypes (CMS); Epithelial-Mesenchymal Transition (EMT); Mitochondria; Reactive oxygen species; SOD2
    DOI:  https://doi.org/10.1186/s12967-023-04341-x
  8. Nat Commun. 2023 Aug 04. 14(1): 4677
    Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer.
    Qiming Zhou, Yao Peng, Fenfen Ji, Huarong Chen, Wei Kang, Lam-Shing Chan, Hongyan Gou, Yufeng Lin, Pingmei Huang, Danyu Chen, Qinyao Wei, Hao Su, Cong Liang, Xiang Zhang, Jun Yu, Chi Chun Wong.
      KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.
    DOI:  https://doi.org/10.1038/s41467-023-39571-6
  9. Gastroenterology. 2023 Aug 02. pii: S0016-5085(23)04837-0. [Epub ahead of print]
    Ceramides increase fatty acid utilization in intestinal progenitors to enhance stemness and increase tumor risk.
    Ying Li, Bhagirath Chaurasia, M Mahidur Rahman, Vincent Kaddai, J Alan Maschek, Jordan A Berg, Joseph L Wilkerson, Ziad S Mahmassani, James Cox, Peng Wei, Peter J Meikle, Donald Atkinson, Liping Wang, Annelise M Poss, Mary C Playdon, Trevor S Tippetts, Esraa M Mousa, Kesara Nittayaboon, Pon Velayutham Anandh Babu, Micah J Drummond, Hans Clevers, James A Shayman, Yoshio Hirabayashi, William L Holland, Jared Rutter, Bruce Edgar, Scott A Summers.
       BACKGROUND AND AIMS: Cancers of the alimentary tract including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs. differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signals of nutritional excess, alter stem cell behaviors to influence cancer risk.
    METHODS: We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism.
    RESULTS: SPT, which diverts dietary fatty- and amino-acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are upregulated in human intestinal adenomas. They produce ceramides which serve as pro-stemness signals that stimulate peroxisome-proliferator activated receptor alpha and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors.
    CONCLUSION: Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.
    Keywords:  Stem cell; ceramides; colorectal cancer; metabolism; sphingolipids
    DOI:  https://doi.org/10.1053/j.gastro.2023.07.017
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