bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–12–24
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. LGR5+ Intestinal Stem Cells Display Sex Dependent Radiosensitivity.
  2. Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.
  3. Method for Two-Dimensional Epithelial Monolayer Formation Derived from Mouse Three-Dimensional Small Intestinal Organoids.
  4. A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer.
  5. Targeting lipid metabolism in cancer metastasis.
  6. Decoding the basis of histological variation in human cancer.
  7. Immunogenic chemotherapy sensitizes RAS-mutated colorectal cancers to immune checkpoint inhibitors.
  8. Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids.
  9. Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer.
  1. bioRxiv. 2023 Dec 07. pii: 2023.12.05.570158. [Epub ahead of print]
    LGR5+ Intestinal Stem Cells Display Sex Dependent Radiosensitivity.
    Ryan C Zitter, Rishi Man Chugh, Payel Bhanja, Subhrajit Saha.
      Radiosensitivity, the susceptibility of cells to ionizing radiation, plays a critical role in understanding the effects of radiation therapy and exposure on tissue health and regeneration. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In mice models of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity are not dependent on sex hormones as we demonstrated similar sex-specific radiosensitivity differences in pediatric mice. In an ex-vivo study, we found that human patient-derived intestinal organoids (PID) derived from males showed higher sensitivity to irradiation compared to females as evidenced by loss of budding crypt, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation induced upregulation of mitochondrial oxidative metabolism in males compared to females' possible mechanism for radiosensitivity differences.
    DOI:  https://doi.org/10.1101/2023.12.05.570158
  2. Dev Cell. 2023 Dec 18. pii: S1534-5807(23)00611-1. [Epub ahead of print]58(24): 2914-2929.e7
    Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice.
    Maja C Funk, Jan G Gleixner, Florian Heigwer, Dominik Vonficht, Erica Valentini, Zeynep Aydin, Elena Tonin, Stefania Del Prete, Sylvia Mahara, Yannick Throm, Jenny Hetzer, Danijela Heide, Oliver Stegle, Duncan T Odom, Angelika Feldmann, Simon Haas, Mathias Heikenwalder, Michael Boutros.
      Low-grade chronic inflammation is a hallmark of ageing, associated with impaired tissue function and disease development. However, how cell-intrinsic and -extrinsic factors collectively establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using mouse organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of inflammaging. At the single-cell level, we found that inflammaging is established differently along the crypt-villus axis, with aged intestinal stem cells (ISCs) strongly upregulating major histocompatibility complex class II (MHC-II) genes. Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility at inflammation-associated loci in vivo and ex vivo, indicating cell-intrinsic inflammatory memory. Mechanistically, we show that the expression of inflammatory genes is dependent on STAT1 signaling. Together, our data identify that intestinal inflammaging in mice is promoted by a cell-intrinsic mechanism, stably propagated by ISCs, and associated with a disbalance in immune homeostasis.
    Keywords:  ISC; ageing; epigenetics; inflammaging; inflammation; interferon; intestinal epithelium; intestinal stem cells; intestine; single-cell analysis
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.013
  3. Methods Mol Biol. 2024 ;2749 73-84
    Method for Two-Dimensional Epithelial Monolayer Formation Derived from Mouse Three-Dimensional Small Intestinal Organoids.
    Yuta Takase, Toshio Takahashi.
      The intestinal epithelium is composed of two distinct structures, namely, the villi and crypts. The base of the crypts contains intestinal stem cells (ISCs), which support the high regenerative capacity of the intestinal epithelium. With the establishment of the three-dimensional (3D) organoid culture method, the cellular and molecular mechanisms of differentiation, proliferation, and maintenance of ISCs have been widely analyzed. However, the sphere-like morphology of the 3D organoids prevents access to the apical side of the epithelium. To overcome this limitation, two-dimensional (2D) monolayer cultures derived from 3D organoids have been attempted; however, 2D culture methods for the mouse small intestine have not been well established. In this study, we developed a simple method that uses only commercially available materials, for the formation of 2D epithelial monolayers from mouse 3D small intestinal organoids. Using this method, confluent 2D epithelial monolayers were established within 4 days. This monolayer showed stable tight junction and included ISCs and differentiated intestinal cells. It also showed physiologically relevant transepithelial electrical resistance values. On the basis of these findings, this method opens a novel platform for analyzing the physiology of the intestinal epithelium, its interaction with microbes, and mechanisms of villus formation.
    Keywords:  2D epithelial monolayer; 3D organoid; Cell differentiation; Intestinal stem cells; Mouse small intestine; Sphere-like morphology; Tight junction; Transepithelial electrical resistance
    DOI:  https://doi.org/10.1007/978-1-0716-3609-1_7
  4. bioRxiv. 2023 Dec 10. pii: 2023.12.10.570854. [Epub ahead of print]
    A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer.
    Slim Mzoughi, Megan Schwarz, Xuedi Wang, Deniz Demircioglu, Gulay Ulukaya, Kevin Mohammed, Federico Di Tullio, Carlos Company, Yuliia Dramaretska, Marc Leushacke, Bruno Giotti, Tamsin Lannagan, Daniel Lozano-Ojalvo, Dan Hasson, Alexander M Tsankov, Owen J Sansom, Jean-Christophe Marine, Nick Barker, Gaetano Gargiulo, Ernesto Guccione.
      Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment 1 . However, the molecular mechanisms underlying resistance to LGR5 + CSCs depletion in colorectal cancer (CRC) 2,3 remain largely elusive. Here, we unveil the existence of a primitive cell state dubbed the oncofetal (OnF) state, which works in tandem with the LGR5 + stem cells (SCs) to fuel tumor evolution in CRC. OnF cells emerge early during intestinal tumorigenesis and exhibit features of lineage plasticity. Normally suppressed by the Retinoid X Receptor (RXR) in mature SCs, the OnF program is triggered by genetic deletion of the gatekeeper APC. We demonstrate that diminished RXR activity unlocks an epigenetic circuity governed by the cooperative action of YAP and AP1, leading to OnF reprogramming. This high-plasticity state is inherently resistant to conventional chemotherapies and its adoption by LGR5 + CSCs enables them to enter a drug-tolerant state. Furthermore, through phenotypic tracing and ablation experiments, we uncover a functional redundancy between the OnF and stem cell (SC) states and show that targeting both cellular states is essential for sustained tumor regression in vivo . Collectively, these findings establish a mechanistic foundation for developing effective combination therapies with enduring impact on CRC treatment.
    DOI:  https://doi.org/10.1101/2023.12.10.570854
  5. Biochim Biophys Acta Rev Cancer. 2023 Dec 13. pii: S0304-419X(23)00200-7. [Epub ahead of print] 189051
    Targeting lipid metabolism in cancer metastasis.
    Gloria Pascual, Blanca Majem, Salvador Aznar-Benitah.
      This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
    Keywords:  Epigenetics; Lipid metabolism; Metastasis; Microenvironment; Therapies
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189051
  6. Nat Rev Cancer. 2023 Dec 22.
    Decoding the basis of histological variation in human cancer.
    Masayuki Fujii, Shigeki Sekine, Toshiro Sato.
      Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.
    DOI:  https://doi.org/10.1038/s41568-023-00648-5
  7. Oncoimmunology. 2023 ;12(1): 2272352
    Immunogenic chemotherapy sensitizes RAS-mutated colorectal cancers to immune checkpoint inhibitors.
    Lucillia Bezu, Oliver Kepp, Guido Kroemer.
      Recent clinical trials have compared the use of different chemotherapeutic regimens as "immune induction therapies" to sensitize cancers to immune checkpoint inhibitors (ICI). Cytotoxic drugs reputed to be inducers of immunogenic cell death (ICD) appeared to be particularly efficient for this purpose. A trial published in Nature Medicine by Thibaudin et al. reveals the capacity of oxaliplatin-based chemotherapy to sensitize RAS-mutant unresectable metastatic colorectal cancer to ICIs blocking CTLA-4 and PD-L1.
    Keywords:  Cancer; immunogenic cell death; immunotherapy
    DOI:  https://doi.org/10.1080/2162402X.2023.2272352
  8. Nat Biomed Eng. 2023 Dec 19.
    Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids.
    Marius F Harter, Timothy Recaldin, Regine Gerard, Blandine Avignon, Yannik Bollen, Cinzia Esposito, Karolina Guja-Jarosz, Kristina Kromer, Adrian Filip, Julien Aubert, Anneliese Schneider, Marina Bacac, Michael Bscheider, Nadine Stokar-Regenscheit, Salvatore Piscuoglio, Joep Beumer, Nikolche Gjorevski.
      Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to capture clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. We analysed the mechanisms of T-cell-mediated damage of neoplastic and donor-matched healthy epithelia at a single-cell resolution using multiplexed immunofluorescence. We found that TCBs that target the epithelial cell-adhesion molecule led to apoptosis in healthy organoids in accordance with clinical observations, and that apoptosis is associated with T-cell activation, cytokine release and intra-epithelial T-cell infiltration. Conversely, tumour organoids were more resistant to damage, probably owing to a reduced efficiency of T-cell infiltration within the epithelium. Patient-derived intestinal organoids can aid the study of immune-epithelial interactions as well as the preclinical and clinical development of cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41551-023-01156-5
  9. Cell Rep Med. 2023 Dec 19. pii: S2666-3791(23)00552-9. [Epub ahead of print]4(12): 101335
    Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer.
    Tao Tan, Dmitri Mouradov, Margaret Lee, Grace Gard, Yumiko Hirokawa, Shan Li, Cong Lin, Fuqiang Li, Huijuan Luo, Kui Wu, Michelle Palmieri, Evelyn Leong, Jordan Clarke, Anuratha Sakthianandeswaren, Helen Brasier, Jeanne Tie, Niall C Tebbutt, Azim Jalali, Rachel Wong, Antony W Burgess, Peter Gibbs, Oliver M Sieber.
      Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.
    Keywords:  colorectal cancer; patient-derived tumor organoid; precision medicine; predictive drug testing
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101335
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