bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2022–05–22
nine papers selected by
Maria-Virginia Giolito, IRFAC/UMR-S1113 INSERM
  1. Mir-675-5p supports hypoxia-induced drug resistance in colorectal cancer cells.
  2. Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review.
  3. SFMBT1 facilitates colon cancer cell metastasis and drug resistance combined with HMG20A.
  4. Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage.
  5. Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients.
  6. RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer.
  7. Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer.
  8. Emerging actionable targets to treat therapy-resistant colorectal cancers.
  9. Drug-tolerant persister cells in cancer therapy resistance.
  1. BMC Cancer. 2022 May 20. 22(1): 567
    Mir-675-5p supports hypoxia-induced drug resistance in colorectal cancer cells.
    Chiara Zichittella, Maria Magdalena Barreca, Aurora Cordaro, Chiara Corrado, Riccardo Alessandro, Alice Conigliaro.
       BACKGROUND: The uncontrolled proliferation of cancer cells determines hypoxic conditions within the neoplastic mass with consequent activation of specific molecular pathways that allow cells to survive despite oxygen deprivation. The same molecular pathways are often the cause of chemoresistance. This study aims to investigate the role of the hypoxia-induced miR-675-5p in 5-Fluorouracil (5-FU) resistance on colorectal cancer (CRC) cells.
    METHODS: CRC cell lines were treated with 5-Fu and incubated in normoxic or hypoxic conditions; cell viability has been evaluated by MTT assay. MiR-675-5p levels were analysed by RT-PCR and loss and gain expression of the miRNA has been obtained by the transfection of miRNA antagomir or miRNA mimic. Total protein expression of different apoptotic markers was analysed through western blot assay. MirWalk 2.0 database search engine was used to investigate the putative targets of the miR-675-5p involved in the apoptotic process. Finally, the luciferase assay was done to confirm Caspase-3 as a direct target of the miR-675-5p.
    RESULTS: Our data demonstrated that hypoxia-induced miR-675-5p counteracts the apoptotic signal induced by 5-FU, thus taking part in the drug resistance response. We showed that the apoptotic markers, cleaved PARP and cleaved caspase-3, increased combining miR-675-5p inhibition with 5-FU treatment. Moreover, we identified pro-caspase-3 among the targets of the miR-675-5p.
    CONCLUSION: Our data demonstrate that the inhibition of hypoxia-induced miR-675-5p combined with 5-FU treatment can enhances drug efficacy in both prolonged hypoxia and normoxia, indicating a possible strategy to partially overcome chemoresistance.
    Keywords:  5-fluorouracil (5-FU); Apoptosis; Colorectal cancer (CRC); Drug resistance; Hypoxia; MicroRNA
    DOI:  https://doi.org/10.1186/s12885-022-09666-2
  2. Cancer Drug Resist. 2021 ;4(4): 946-964
    Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review.
    Shogo Ozawa, Toshitaka Miura, Jun Terashima, Wataru Habano.
      Treatment with pharmacological drugs for colorectal cancer (CRC) remains unsatisfactory. A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs, creating an urgent issue. In this review, we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness. Our review presents the following five major causes of irinotecan resistance in human CRC: (1) cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter, ABCG2; (2) cellular irinotecan resistance is also induced in association with a nuclear receptor, pregnane/steroid X receptor (PXR/SXR), which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38; (3) irinotecan-resistant cells possess either reduced DNA topoisomerase I (Top1) expression at both the mRNA and protein levels or Top1 missense mutations; (4) alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs; and (5) CRC stem cells are the most difficult targets to successfully treat CRC. In the clinical setting, CRC gradually develops resistance to initially effective irinotecan-based therapy. To solve this problem, several clinical trials, such as irinotecan plus cetuximab vs. cetuximab monotherapy, have been conducted. Another clinical trial on irinotecan plus guadecitabine, a DNA-methyltransferase inhibitor, has also been conducted.
    Keywords:  ABCG2; DNA topoisomerase I; Drug resistance; anti-cancer drugs; cancer stem cells; colorectal cancer; epigenetics; irinotecan
    DOI:  https://doi.org/10.20517/cdr.2021.82
  3. Cell Death Discov. 2022 May 16. 8(1): 263
    SFMBT1 facilitates colon cancer cell metastasis and drug resistance combined with HMG20A.
    Ruijun Pan, Dingye Yu, Jiajia Hu, Xiao Yang, Chenxing Wang, Luyang Zhang, Pei Xue, Jing Sun, Xiaoping Zhang, Wei Cai.
      In colorectal cancer (CRC), the development of reagents that increase sensitivity to chemotherapeutic agents could prevent drug resistance and improve patient survival. Scm-like with four malignant brain tumor domains 1 (SFMBT1) is up-regulated in CRC tumor tissues and cells and may be associated with drug resistance. We detected the expression of SFMBT1 in CRC tissue microarrays by immunohistochemistry. The role of SFMBT1 in the migration, proliferation and invasion of CRC or resistance to 5-fluorouracil (5-FU) was determined using scratch assay, colony formation and Transwell assay. Fluorescence co-localization and immunoprecipitation were used to analyze the correlation between SFMBT1 and high mobility group domain-containing protein 20 A (HMG20A). Xenograft experiments were conducted to investigate the role of SFMBT1 and HMG20A in tumor growth and metastasis in vivo. We found that SFMBT1 is up-regulated in CRC and its expression is further amplified in 5-FU resistance. SFMBT1 drives 5-FU resistance and CRC proliferation, migration and invasion. Correlation analysis shows that SFMBT1 and HMG20A are positively correlated. Mechanistically, fluorescence co-localization and immunoprecipitation assay indicate an interaction between SFMBT1 and HMG20A. Depletion of SFMBT1 down-regulates HMG20A downstream. These results were verified by murine xenograft and lung metastasis models. Our results indicate that the SFMBT1/HMG20A axis could be targeted to increase the resistance of CRC cells to 5-FU.
    DOI:  https://doi.org/10.1038/s41420-022-01057-7
  4. Cancer Res. 2022 May 16. 82(10): 1953-1968
    Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage.
    Maria C Heinz, Niek A Peters, Koen C Oost, Rik G H Lindeboom, Lisa van Voorthuijsen, Arianna Fumagalli, Mirjam C van der Net, Gustavo de Medeiros, Joris H Hageman, Ingrid Verlaan-Klink, Inne H M Borel Rinkes, Prisca Liberali, Martijn Gloerich, Jacco van Rheenen, Michiel Vermeulen, Onno Kranenburg, Hugo J G Snippert.
      Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases.
    SIGNIFICANCE: Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases. See related commentary by LeBleu, p. 1870.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0933
  5. Nat Commun. 2022 May 19. 13(1): 2800
    Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients.
    Ori Hassin, Nishanth Belugali Nataraj, Michal Shreberk-Shaked, Yael Aylon, Rona Yaeger, Giulia Fontemaggi, Saptaparna Mukherjee, Martino Maddalena, Adi Avioz, Ortal Iancu, Giuseppe Mallel, Anat Gershoni, Inna Grosheva, Ester Feldmesser, Shifra Ben-Dor, Ofra Golani, Ayal Hendel, Giovanni Blandino, David Kelsen, Yosef Yarden, Moshe Oren.
      The TP53 gene is mutated in approximately 60% of all colorectal cancer (CRC) cases. Over 20% of all TP53-mutated CRC tumors carry missense mutations at position R175 or R273. Here we report that CRC tumors harboring R273 mutations are more prone to progress to metastatic disease, with decreased survival, than those with R175 mutations. We identify a distinct transcriptional signature orchestrated by p53R273H, implicating activation of oncogenic signaling pathways and predicting worse outcome. These features are shared also with the hotspot mutants p53R248Q and p53R248W. p53R273H selectively promotes rapid CRC cell spreading, migration, invasion and metastasis. The transcriptional output of p53R273H is associated with preferential binding to regulatory elements of R273 signature genes. Thus, different TP53 missense mutations contribute differently to cancer progression. Elucidation of the differential impact of distinct TP53 mutations on disease features may make TP53 mutational information more actionable, holding potential for better precision-based medicine.
    DOI:  https://doi.org/10.1038/s41467-022-30481-7
  6. Nat Commun. 2022 May 19. 13(1): 2791
    RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer.
    Adam E Hall, Sebastian Öther-Gee Pohl, Patrizia Cammareri, Stuart Aitken, Nicholas T Younger, Michela Raponi, Caroline V Billard, Alfonso Bolado Carrancio, Aslihan Bastem, Paz Freile, Fiona Haward, Ian R Adams, Javier F Caceres, Paula Preyzner, Alex von Kriegsheim, Malcolm G Dunlop, Farhat V Din, Kevin B Myant.
      Tumour cell plasticity is a major barrier to the efficacy of targeted cancer therapies but the mechanisms that mediate it are poorly understood. Here, we identify dysregulated RNA splicing as a key driver of tumour cell dedifferentiation in colorectal cancer (CRC). We find that Apc-deficient CRC cells have dysregulated RNA splicing machinery and exhibit global rewiring of RNA splicing. We show that the splicing factor SRSF1 controls the plasticity of tumour cells by controlling Kras splicing and is required for CRC invasion in a mouse model of carcinogenesis. SRSF1 expression maintains stemness in human CRC organoids and correlates with cancer stem cell marker expression in human tumours. Crucially, partial genetic downregulation of Srsf1 does not detrimentally affect normal tissue homeostasis, demonstrating that tumour cell plasticity can be differentially targeted. Thus, our findings link dysregulation of the RNA splicing machinery and control of tumour cell plasticity.
    DOI:  https://doi.org/10.1038/s41467-022-30489-z
  7. Cancer Drug Resist. 2021 ;4(2): 424-452
    Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer.
    Wing-Kee Lee, Thévenod Frank.
      Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets, but also for inhibiting apoptotic cell death cues, such as removal of proapoptotic signals. Several cell populations exhibiting the MDR phenotype co-exist within a tumor, such as cells forming the bulk tumor cell mass, cancer stem cells, and cancer persister cells. The key to regulation of ABCB1 expression is the cellular transcriptional machinery. Developmental signaling pathways (e.g, Hedgehog, Notch, Wnt/β-catenin, TGFβ, PITX2) are pivotal in governing cell proliferation, survival, differentiation and guiding cell migration during embryogenesis, and their reactivation during carcinogenesis, which is of particular significance for tumor initiation, progression, and metastasis, also leads to the upregulation of ABCB1. These pathways also drive and maintain cancer cell stemness, for which ABCB1 is used as a marker. In this review, the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.
    Keywords:  ABC transporters; Drug resistance; transforming growth factor beta; tumor cell biology; tumor heterogeneity
    DOI:  https://doi.org/10.20517/cdr.2020.114
  8. Cancer Drug Resist. 2022 ;5(1): 36-63
    Emerging actionable targets to treat therapy-resistant colorectal cancers.
    Emanuela Grassilli, Maria Grazia Cerrito.
      In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a "big killer" mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.
    Keywords:  BRAF; Colorectal cancer; EGFR; ERBB2; MET; chemotherapy; gut microbiota; immune checkpoint inhibitors; kinase inhibitors; resistance; target therapy
    DOI:  https://doi.org/10.20517/cdr.2021.96
  9. Cancer Res. 2022 May 18. pii: canres.3844.2021. [Epub ahead of print]
    Drug-tolerant persister cells in cancer therapy resistance.
    Pavan Kumar Dhanyamraju, Todd D Schell, Shantu Amin, Gavin P Robertson.
      One of the current stumbling blocks in our fight against cancer is the development of acquired resistance to therapy, which is attributable to approximately ninety percent of cancer-related deaths. Undercutting this process during treatment could significantly improve cancer management. In many cases, drug resistance is mediated by a drug-tolerant persister (DTP) cell subpopulation present in tumors, often referred to as persister cells. This review provides a summary of currently known persister cell subpopulations and approaches to target them. A specific DTP cell subpopulation with elevated levels of aldehyde dehydrogenase (ALDH) activity has stem cell-like characteristics and a high level of plasticity, enabling them to switch rapidly between high and low ALDH activity. Further studies are required to fully elucidate the functions of ALDH-high DTP cells, how they withstand drug concentrations that kill other cells, and how they rapidly adapt under levels of high cellular stress and eventually lead to more aggressive, recurrent, and drug-resistant cancer. Furthermore, this review addresses the processes used by the ALDH-high persister cell subpopulation to enable cancer progression, the ALDH isoforms important in these processes, interactions of ALDH-high DTPs with the tumor microenvironment, and approaches to therapeutically modulate this subpopulation in order to more effectively manage cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3844
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