bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2022–10–30
24 papers selected by
Maria-Virginia Giolito, Free University of Brussels
  1. Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability.
  2. Intestinal epithelial BLT1 promotes mucosal repair.
  3. Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer.
  4. MicroRNA-19b Plays a Key Role in 5-Fluorouracil Resistance and Predicts Tumor Progression in Locally Advanced Rectal Cancer Patients.
  5. The Interplay between Anti-Angiogenics and Immunotherapy in Colorectal Cancer.
  6. N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis.
  7. Downregulation of iNOS/NO promotes epithelial-mesenchymal transition and metastasis in colorectal cancer.
  8. A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy.
  9. Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells.
  10. Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer.
  11. Adherens junction proteins on the move-From the membrane to the nucleus in intestinal diseases.
  12. Impact of a haplotype (composed of the APC, KRAS, and TP53 genes) on colorectal adenocarcinoma differentiation and patient prognosis.
  13. Inhibition of Wnt signaling in colon cancer cells via an oral drug that facilitates TNIK degradation.
  14. Phenotypic plasticity and genetic control in colorectal cancer evolution.
  15. Modulation of tumor-associated macrophages in colitis-associated colorectal cancer.
  16. Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.
  17. The co-evolution of the genome and epigenome in colorectal cancer.
  18. Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms.
  19. FOXL1 + Telocytes in mouse colon orchestrate extracellular matrix biodynamics and wound repair resolution.
  20. Farnesoid-X receptor as a therapeutic target for inflammatory bowel disease and colorectal cancer.
  21. CDX2 as a Predictive Biomarker Involved in Immunotherapy Response Suppresses Metastasis through EMT in Colorectal Cancer.
  22. Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies.
  23. Generation of human colon organoids from healthy and inflammatory bowel disease mucosa.
  24. Role of a lipid metabolism-related lncRNA signature in risk stratification and immune microenvironment for colon cancer.
  1. Cancers (Basel). 2022 Oct 11. pii: 4974. [Epub ahead of print]14(20):
    Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability.
    Beatrice Borelli, Carlotta Antoniotti, Martina Carullo, Marco Maria Germani, Veronica Conca, Gianluca Masi.
      Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.
    Keywords:  POLE mutation; deficient mismatch repair; high microsatellite instability; immune-checkpoint inhibitors; metastatic colorectal cancer
    DOI:  https://doi.org/10.3390/cancers14204974
  2. JCI Insight. 2022 Oct 27. pii: e162392. [Epub ahead of print]
    Intestinal epithelial BLT1 promotes mucosal repair.
    Shusaku Hayashi, Chithra K Muraleedharan, Makito Oku, Sunil Tomar, Simon P Hogan, Miguel Quiros, Charles A Parkos, Asma Nusrat.
      Acute and chronic intestinal inflammation is associated with epithelial damage, resulting in mucosal wounds in the forms of erosions and ulcers in the intestinal tract. Intestinal epithelial cells (IECs) and immune cells in the wound milieu secrete cytokines and lipid mediators to influence repair. Leukotriene B4 (LTB4), a lipid chemokine, binds to its receptor BLT1 and promotes migration of immune cells to sites of active inflammation, however a role for intestinal epithelial BLT1 during mucosal wound repair is not known. Here we report that BLT1 is expressed in IECs both in vitro and in vivo, where it functions as a receptor not only for LTB4 but also for another ligand Resolvin E1. Intestinal epithelial BLT1 expression is increased when epithelial cells are exposed to an inflammatory microenvironment. Using human and murine primary colonic epithelial cells, we reveal that LTB4-BLT1 axis promotes epithelial migration and proliferation leading to accelerated epithelial wound repair. Furthermore, in vivo intestinal wound repair experiments in BLT1-deficient mice and bone marrow chimeras demonstrate an important contribution of epithelial BLT1 during colonic mucosal wound repair. Taken together, our findings show a novel pro-repair in IEC mechanism mediated by BLT1 signaling.
    Keywords:  Gastroenterology; Inflammation; Inflammatory bowel disease
    DOI:  https://doi.org/10.1172/jci.insight.162392
  3. Med Oncol. 2022 Oct 29. 40(1): 3
    Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer.
    Adarsh Kumar, Ankit Kumar Singh, Harshwardhan Singh, Suresh Thareja, Pradeep Kumar.
      Thymidylate synthase is the rate-limiting enzyme required for DNA synthesis and overexpression of this enzyme causes resistance to cancer cells. Long treatments with 5-FU cause resistance to Thymidylate synthase targeting drugs. We have also compiled different mechanisms of drug resistance including autophagy and apoptosis, drug detoxification and ABC transporters, drug efflux, signaling pathways (AKT/PI3K, RAS-MAPK, WNT/β catenin, mTOR, NFKB, and Notch1 and FOXM1) and different genes associated with resistance in colorectal cancer. We can overcome 5-FU resistance in cancer cells by regulating thymidylate synthase by natural products (Coptidis rhizoma), HDAC inhibitors, mTOR inhibitors, Folate antagonists, and several other drugs which have been used in combination with TS inhibitors. This review is a compilation of different approaches reported for the regulation of thymidylate synthase to overcome resistance in colorectal cancer cells.
    Keywords:  5-FU; Colorectal cancer; Regulation; Resistance; Thymidylate synthase
    DOI:  https://doi.org/10.1007/s12032-022-01864-z
  4. Int J Mol Sci. 2022 Oct 18. pii: 12447. [Epub ahead of print]23(20):
    MicroRNA-19b Plays a Key Role in 5-Fluorouracil Resistance and Predicts Tumor Progression in Locally Advanced Rectal Cancer Patients.
    Andrea Santos, Ion Cristóbal, Jaime Rubio, Cristina Caramés, Melani Luque, Marta Sanz-Álvarez, Sandra Zazo, Juan Madoz-Gúrpide, Federico Rojo, Jesus García-Foncillas.
      The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome and pathological response to preoperative CRT in this disease. Moreover, it has been discovered that this miR increases its expression in 5-FU resistant colon cancer cells after 5-FU exposure. Despite the fact that these observations suggest a functional role of miR-19b modulating 5-FU response of LARC cells, this issue still remains to be clarified. Here, we show that downregulation of miR-19b enhances the antitumor effects of 5-FU treatment. Moreover, ectopic miR-19b modulation was able to restore sensitivity to 5-FU treatment using an acquired resistant model to this compound. Notably, we also evaluated the potential clinical impact of miR-19b as a predictive marker of disease progression after tumor surgery resection in LARC patients, observing that miR-19b overexpression significantly anticipates patient recurrence in our cohort (p = 0.002). Altogether, our findings demonstrate the functional role of miR-19b in the progressively decreasing sensitivity to 5-FU treatment and its potential usefulness as a therapeutic target to overcome 5-FU resistance, as well as its clinical impact as predictor of tumor progression and relapse.
    Keywords:  5-FU resistance; locally advanced rectal cancer; miR-19b; progression
    DOI:  https://doi.org/10.3390/ijms232012447
  5. Life (Basel). 2022 Oct 06. pii: 1552. [Epub ahead of print]12(10):
    The Interplay between Anti-Angiogenics and Immunotherapy in Colorectal Cancer.
    Brigida Anna Maiorano, Alessandro Parisi, Evaristo Maiello, Davide Ciardiello.
      Angiogenesis, a hallmark of cancer, plays a fundamental role in colorectal cancer (CRC). Anti-angiogenic drugs and chemotherapy represent a standard of care for treating metastatic disease. Immune checkpoint inhibitors (ICIs) have changed the therapeutic algorithm of many solid tumors. However, the efficacy of ICIs is limited to mCRC patients carrying microsatellite instability (MSI-H), which represent approximately 3-5% of mCRC. Emerging evidence suggests that anti-angiogenic drugs could exhibit immunomodulatory properties. Thus, there is a strong rationale for combining anti-angiogenics and ICIs to improve efficacy in the metastatic setting. Our review summarizes the pre-clinical and clinical evidence regarding the combination of anti-angiogenics and ICIs in mCRC to deepen the possible application in daily clinical practice.
    Keywords:  CRC; ICIs; angiogenesis; anti-angiogenics; bevacizumab; colorectal cancer; immune checkpoint inhibitors; immunotherapy; nivolumab; pembrolizumab
    DOI:  https://doi.org/10.3390/life12101552
  6. Mol Ther. 2022 Oct 28. pii: S1525-0016(22)00624-4. [Epub ahead of print]
    N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis.
    Ziyou Lin, Arabella H Wan, Lei Sun, Heng Liang, Yi Niu, Yuan Deng, Shijia Yan, Qiao-Ping Wang, Xianzhang Bu, Xiaolei Zhang, Kunhua Hu, Guohui Wan, Weiling He.
      N6-methyladenosine (m6A) is the most pervasive RNA modification and is recognized as a novel epigenetic regulation in RNA metabolism. Although the m6A modification involves various physiological processes, its roles in drug-resistance in colorectal cancer (CRC) still remain unknown. We analyzed the RNA expression profile of m6A/A (%) with MRM mass spectrometry in human 5-fluorouracil (5-FU) resistant CRC tissues, and used the m6A RNA immunoprecipitation assay to validate the m6A-regulated target. Our results have shown that the m6A demethylase FTO was up-regulated in human primary and 5-FU resistant CRC. Depletion of FTO decreased cell growth, colony formation and metastasis in 5-FU resistant CRC cells in vitro and in vivo. Mechanistically, we identified SIVA1, a critical apoptotic gene, as a key downstream target of the FTO-mediated m6A demethylation. The m6A demethylation of SIVA1 at the CDS region induced its mRNA degradation via a YTHDF2-dependent mechanism. The SIVA1 levels were negatively correlated with the FTO levels in clinical CRC tissues. Notably, inhibition of FTO significantly reduced the tolerance of 5-FU in 5-FU-resistant CRC cells via the FTO-SIVA1 axis, whereas SIVA1-depletion could restore the m6A-dependent 5-FU sensitivity in CRC cells. In summary, our findings demonstrate a critical role of FTO as an m6A demethylase enhancing chemo-resistance in CRC cells, and suggest that FTO inhibition may restore the sensitivity of chemo-resistant CRC cells to 5-FU.
    Keywords:  Colorectal cancer; FTO; N6-methyladenosine; SIVA1; chemo-resistance
    DOI:  https://doi.org/10.1016/j.ymthe.2022.10.012
  7. Mol Cancer Res. 2022 Oct 28. pii: MCR-22-0509. [Epub ahead of print]
    Downregulation of iNOS/NO promotes epithelial-mesenchymal transition and metastasis in colorectal cancer.
    Qiang Du, Silvia Liu, Kun Dong, Xiao Cui, Jing Luo, David A Geller.
      Metastasis is the major cause of cancer-related death in patients with colorectal cancer (CRC). Although inducible nitric oxide synthase (iNOS) is a crucial regulator of cancer development and progression, its roles in epithelial-mesenchymal transition (EMT) and the pathogenesis of metastatic CRC have not been fully investigated. Primary CRC and liver metastatic tissue specimens were analyzed showing 90% of liver metastatic CRC with reduced-expressions of iNOS compared with 6% of primary CRC. TCGA database analyses via cBioPortal reveal that mRNA expression of iNOS negatively correlated with selected EMT markers in CRC in a cancer-type dependent manner. The transcriptomic profiling (RNA-Seq data) indicates that iNOS knockdown in SW480 CRC cells induced an EMT program with upregulated expression of selected stem-cell markers. iNOS knockdown did not alter E-cadherin mRNA expression but re-localized it from membrane to cytoplasm through iNOS-GATA4-Crb2-E-cadherin pathway. iNOS knockdown induced a change in cell morphology, and promoted cell invasion and migration in vitro, and metastasis in vivo. Implications: iNOS downregulation-induced pathway networks mediate the EMT program and metastasis. As an EMT-inducer, the reduced-iNOS may serve as a potential therapeutic target for CRC patients.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0509
  8. Adv Sci (Weinh). 2022 Oct 26. e2204513
    A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy.
    Zihao Pan, Jun Zheng, Jiebin Zhang, Jiatong Lin, Jianguo Lai, Zejian Lyu, Huolun Feng, Junjiang Wang, Deqing Wu, Yong Li.
      Oxaliplatin is commonly used in chemotherapeutic regimens for colorectal cancer (CRC) after surgical resection. However, acquired chemoresistance seriously affects the curative effect in CRC patients, and the mechanism is still unclear. Here, a circular RNA, circATG4B is identified, which plays an important role in oxaliplatin resistance in CRC. circATG4B expression is found to be increased in exosomes secreted by oxaliplatin-resistant CRC cells. In addition, the results suggest that circATG4B induces oxaliplatin resistance by promoting autophagy. Further in vivo and in vitro studies indicate that the effect of circATG4B is attributed to its potential to encode a novel protein, circATG4B-222aa. Next, circATG4B-222aa is found to function as a decoy to competitively interact with TMED10 and prevent TMED10 from binding to ATG4B, which leads to increased autophagy followed by induction of chemoresistance. Therefore, this study reveals that exosomal circATG4B participates in the decreased chemosensitivity of CRC cells, providing a new rationale for a potential therapeutic target for oxaliplatin resistance in CRC.
    Keywords:  autophagy; chemoresistance; circular RNA; colorectal cancer (CRC)
    DOI:  https://doi.org/10.1002/advs.202204513
  9. Cancers (Basel). 2022 Oct 12. pii: 4993. [Epub ahead of print]14(20):
    Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells.
    Claudia Maresca, Giulia Di Maggio, Carmine Stolfi, Federica Laudisi, Marco Colella, Teresa Pacifico, Antonio Di Grazia, Davide Di Fusco, Daniele Congiu, Andrea Martina Guida, Giuseppe Sica, Ivan Monteleone, Giovanni Monteleone.
      Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC.
    Keywords:  Smad; colonic neoplasia; cytokines; transcription factors
    DOI:  https://doi.org/10.3390/cancers14204993
  10. Biomedicines. 2022 Sep 20. pii: 2343. [Epub ahead of print]10(10):
    Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer.
    Julian L Goggi, Shivashankar Khanapur, Siddesh V Hartimath, Boominathan Ramasamy, Peter Cheng, Hui-Xian Chin, Jun-Rong Tang, You-Yi Hwang, Edward G Robins.
      Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI-chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [18F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (TEM) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [18F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing TEM cells responsible for durable immunological memory response to combination therapy in vivo.
    Keywords:  Kv1.3 potassium channel; chemotherapy; effector memory T-cell; immune checkpoint
    DOI:  https://doi.org/10.3390/biomedicines10102343
  11. Front Cell Dev Biol. 2022 ;10 998373
    Adherens junction proteins on the move-From the membrane to the nucleus in intestinal diseases.
    Lindyann R Lessey, Shaiya C Robinson, Roopali Chaudhary, Juliet M Daniel.
      The function and structure of the mammalian epithelial cell layer is maintained by distinct intercellular adhesion complexes including adherens junctions (AJs), tight junctions, and desmosomes. The AJ is most integral for stabilizing cell-cell adhesion and conserving the structural integrity of epithelial tissues. AJs are comprised of the transmembrane protein E-cadherin and cytoplasmic catenin cofactors (α, β, γ, and p120-catenin). One organ where malfunction of AJ is a major contributor to disease states is the mammalian intestine. In the intestine, cell-cell adhesion complexes work synergistically to maintain structural integrity and homeostasis of the epithelium and prevent its malfunction. Consequently, when AJ integrity is compromised in the intestinal epithelium, the ensuing homeostatic disruption leads to diseases such as inflammatory bowel disease and colorectal carcinoma. In addition to their function at the plasma membrane, protein components of AJs also have nuclear functions and are thus implicated in regulating gene expression and intracellular signaling. Within the nucleus, AJ proteins have been shown to interact with transcription factors such as TCF/LEF and Kaiso (ZBTB33), which converge on the canonical Wnt signaling pathway. The multifaceted nature of AJ proteins highlights their complexity in modulating homeostasis and emphasizes the importance of their subcellular localization and expression in the mammalian intestine. In this review, we summarize the nuclear roles of AJ proteins in intestinal tissues; their interactions with transcription factors and how this leads to crosstalk with canonical Wnt signaling; and how nuclear AJ proteins are implicated in intestinal homeostasis and disease.
    Keywords:  Adherens Junction; E-cadherin; Kaiso; Wnt signaling; catenins; colon cancer; inflammatory bowel disease
    DOI:  https://doi.org/10.3389/fcell.2022.998373
  12. Cancer Genet. 2022 Oct 14. pii: S2210-7762(22)00130-2. [Epub ahead of print]268-269 115-123
    Impact of a haplotype (composed of the APC, KRAS, and TP53 genes) on colorectal adenocarcinoma differentiation and patient prognosis.
    Xinyu Peng, Tao Zhang, Xiongjie Jia, Tong Wang, Hengxue Lin, Gang Li, Riheng Li, Aimin Zhang.
       BACKGROUND: Many types of gene mutation are associated with the drug resistance of cancer cells. XELOX is a new and efficient surgical adjuvant chemotherapy for colorectal adenocarcinoma. However, drug-resistant related genetic mutations associated with this treatment remain unknown.
    METHODS: Next-generation sequencing (NGS) was performed on 36 colorectal cancer patients to identify mutations among patients with residual tumors following preoperative chemotherapy. Enrichment and prognosis of these mutations were evaluated in a TCGA cohort. The pathology of cases with poor prognosis-related mutations was also determined.
    RESULTS: A sequence of SNPs associated with the APC, KRAS, and TP53 genes in 13 of 19 subjects with residual tumors after preoperative chemotherapy was identified. Using survival analysis data from 317 cases in the TCGA database, a prognosis-related haplotype composed of SNPs from APC, KRAS, and TP53 was assembled. Colorectal cancer patients with these mutations had a lower 5-year tumor-specific survival rate than those without (p < 0.05). Most patients with these mutations were at a higher clinical stage (III-IV) of disease. Enrolled subjects with the identified haplotype tended to have poor cancer cell differentiation.
    CONCLUSIONS: The prognosis-related haplotype can be used as a marker of drug resistance and prognosis in colorectal cancer patients after preoperative chemotherapy.
    Keywords:  Colorectal adenocarcinoma; Differentiation; Haplotype; Prognosis
    DOI:  https://doi.org/10.1016/j.cancergen.2022.10.002
  13. Mol Cancer Ther. 2022 Oct 27. pii: MCT-21-0801. [Epub ahead of print]
    Inhibition of Wnt signaling in colon cancer cells via an oral drug that facilitates TNIK degradation.
    Kun Zhou, Jae Eun Cheong, Subrahmanian Tarakkad Krishnaji, Aram Ghalali, Haojie Fu, Lufei Sui, Catherine Alix-Panabieres, Laure Cayrefourcq, Diane Bielenberg, Lijun Sun, Bruce R Zetter.
      We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong anti-cancer activity in multiple types of cancer cells, especially colorectal cancer (CRC). In this report, we provide evidence that OBD9 suppresses CRC growth by interfering with the Wnt signaling pathway, a main driver of cell growth in CRC. Specifically, we find that OBD9 induces autophagic degradation of TNIK (traf2 and Nck- interacting kinase), which promotes T cell factor-4 (TCF4)/beta-catenin-mediated gene expression. Thus, OBD9 as a TNIK inhibitor blocks Wnt/beta-catenin signaling at the final step of transcriptional activation. We suggest that OBD9 provides a potential novel autophagy-mediated, Wnt-damping therapeutic strategy for the treatment of CRC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-21-0801
  14. Nature. 2022 Oct 26.
    Phenotypic plasticity and genetic control in colorectal cancer evolution.
    Jacob Househam, Timon Heide, George D Cresswell, Inmaculada Spiteri, Chris Kimberley, Luis Zapata, Claire Lynn, Chela James, Maximilian Mossner, Javier Fernandez-Mateos, Alessandro Vinceti, Ann-Marie Baker, Calum Gabbutt, Alison Berner, Melissa Schmidt, Bingjie Chen, Eszter Lakatos, Vinaya Gunasri, Daniel Nichol, Helena Costa, Miriam Mitchinson, Daniele Ramazzotti, Benjamin Werner, Francesco Iorio, Marnix Jansen, Giulio Caravagna, Chris P Barnes, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Andrea Sottoriva, Trevor A Graham.
      Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.
    DOI:  https://doi.org/10.1038/s41586-022-05311-x
  15. J Cell Physiol. 2022 Oct 27.
    Modulation of tumor-associated macrophages in colitis-associated colorectal cancer.
    Yingjie Dong, Qiuli Yang, Ruiying Niu, Zhiyuan Zhang, Yijin Huang, Yujing Bi, Guangwei Liu.
      Intestinal macrophages are the most abundant immune cells in the small and large intestine, which maintain intestinal homeostasis by clearing invading bacteria and dead cells, secreting anti-inflammatory cytokines, and inducing tolerance to symbiotic bacteria and food particles. In addition, as antigen-presenting cells, they also participate in eliciting adaptive immune responses through bridging innate immune responses. After the intestinal homeostasis is disrupted, the damaged or apoptotic intestinal epithelial cells cannot be effectively cleared, and the infection of exogenous pathogens and leakage of endogenous antigens lead to persistent intestinal inflammation. Long-term chronic inflammation is one of the important causes of colitis-associated carcinogenesis (CAC). Tumor microenvironment (TME) is gradually formed around tumor cells, in which tumor associated macrophage (TAMs) is not only the builder, but also regulated by TME. This review just briefly summarized the role of intestinal macrophages under physiological and pathological inflammatory and cancerous conditions, and current therapeutic strategies for intestinal diseases targeting macrophages.
    Keywords:  cancer; colitis; colitis-associated colorectal cancer; colorectal cancer; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1002/jcp.30906
  16. Mol Cancer Ther. 2022 Oct 22. pii: MCT-22-0301. [Epub ahead of print]
    Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.
    Hajrah Khawaja, Rebecca Briggs, Cheryl H Latimer, Mustasin Rassel, Daryl Griffin, Lyndsey Hanson, Alberto Bardelli, Federica Di Nicolantonio, Simon S McDade, Christopher J Scott, Shauna Lambe, Manisha Maurya, Andreas U Lindner, Jochen Hm Prehn, Jose Sousa, Chris Winnington, Melissa J LaBonte, Sarah J Ross, Sandra Van Schaeybroeck.
      Novel covalent inhibitors of KRASG12C have shown limited response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Small molecule KRASG12C inhibitors AZ'1569 and AZ'8037 were employed. To identify novel candidate combination strategies for AZ'1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo. AZ'1569-resistant CRC cells were generated and characterised. We found that response to AZ'1569 was heterogeneous across the KRASG12CMT models. AZ'1569 was ineffective at inducing apoptosis when used as single-agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ'1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ'1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ'1569. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12CMT xenografts. Finally, AZ'1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ'1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Taken together, combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0301
  17. Nature. 2022 Oct 26.
    The co-evolution of the genome and epigenome in colorectal cancer.
    Timon Heide, Jacob Househam, George D Cresswell, Inmaculada Spiteri, Claire Lynn, Maximilian Mossner, Chris Kimberley, Javier Fernandez-Mateos, Bingjie Chen, Luis Zapata, Chela James, Iros Barozzi, Ketevan Chkhaidze, Daniel Nichol, Vinaya Gunasri, Alison Berner, Melissa Schmidt, Eszter Lakatos, Ann-Marie Baker, Helena Costa, Miriam Mitchinson, Rocco Piazza, Marnix Jansen, Giulio Caravagna, Daniele Ramazzotti, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Trevor A Graham, Andrea Sottoriva.
      Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4-7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.
    DOI:  https://doi.org/10.1038/s41586-022-05202-1
  18. Cancers (Basel). 2022 Oct 11. pii: 4984. [Epub ahead of print]14(20):
    Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms.
    Kristin Pape, Anna J Lößner, Doreen William, Tabea Czempiel, Elke Beyreuther, Anna Klimova, Claudia Lehmann, Tim Schmäche, Sebastian R Merker, Max Naumann, Anne-Marlen Ada, Franziska Baenke, Therese Seidlitz, Rebecca Bütof, Antje Dietrich, Mechthild Krause, Jürgen Weitz, Barbara Klink, Cläre von Neubeck, Daniel E Stange.
      Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient's tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.
    Keywords:  3D cell culture; ATM; DNA damage response; chemoradiotherapy; colorectal cancer; patient-derived organoid; proton radiation; translational radio-oncology
    DOI:  https://doi.org/10.3390/cancers14204984
  19. J Proteomics. 2022 Oct 19. pii: S1874-3919(22)00279-2. [Epub ahead of print] 104755
    FOXL1 + Telocytes in mouse colon orchestrate extracellular matrix biodynamics and wound repair resolution.
    Veronique Pomerleau, Vilcy Reyes Nicolas, Carla-Marie Jurkovic, Nathalie Faucheux, Marc-Antoine Lauzon, François-Michel Boisvert, Nathalie Perreault.
      Recent studies have identified FoxL1+telocytes (TCFoxL1+) as key players in gut epithelial-mesenchymal interactions which can determine the colonic microenvironment. Bone morphogenetic protein signaling disruption in TCFoxL1+ alters the physical and cellular microenvironment and leads to colon pathophysiology. This suggests a role for TCFoxL1+ in stromagenesis, but it is hard to identify the specific contribution of TCFoxL1+ when analyzing whole tissue profiling studies. We performed ex vivo deconstruction of control and BmpR1a△FoxL1+ colon samples, isolated the mesenchyme-enriched fractions, and determined the protein composition of the in vivo extracellular matrix (ECM) to analyze microenvironment variation. Matrisomic analysis of mesenchyme fractions revealed modulations in ECM proteins with functions associated with innate immunity, epithelial wound healing, and the collagen network. These results show that TCFoxL1+ is critical in orchestrating the biodynamics of the colon ECM. TCFoxL1+ disfunction reprograms the gut's microenvironment and drives the intestinal epithelium toward colonic pathologies. SIGNIFICANCE: In this study, the method that was elected to isolate ECM proteins might not encompass the full extent of ECM proteins in a tissue, due to the protocol chosen, as this protocol by Naba et al., targets more the insoluble part of the matrisome and eliminates the more soluble components in the first steps. However, this ECM-enrichment strategy represents an improvement and interesting avenue to study ECM proteins in the colon compared to total tissue analysis with a background of abundant cellular protein. Thus, the matrisomic approach presented in this study, and its target validation delivered a broader evaluation of the matrix remodeling occurring in the colonic sub-epithelial mesenchyme of the BmpR1a△FoxL1+ mouse model.
    Keywords:  BMP signaling; Epithelial-mesenchymal interaction; Extracellular matrix; FoxL1(+)-Telocytes; Matrisome; Mechanical microenvironment
    DOI:  https://doi.org/10.1016/j.jprot.2022.104755
  20. Front Pharmacol. 2022 ;13 1016836
    Farnesoid-X receptor as a therapeutic target for inflammatory bowel disease and colorectal cancer.
    Mengjiao Zhou, Danfeng Wang, Xiang Li, Ying Cao, Chengxue Yi, Dickson Kofi Wiredu Ocansey, Yuling Zhou, Fei Mao.
      Farnesoid-X receptor (FXR), as a nuclear receptor activated by bile acids, is a vital molecule involved in bile acid metabolism. Due to its expression in immune cells, FXR has a significant effect on the function of immune cells and the release of chemokines when immune cells sense changes in bile acids. In addition to its regulation by ligands, FXR is also controlled by post-translational modification (PTM) activities such as acetylation, SUMOylation, and methylation. Due to the high expression of FXR in the liver and intestine, it significantly influences intestinal homeostasis under the action of enterohepatic circulation. Thus, FXR protects the intestinal barrier, resists bacterial infection, reduces oxidative stress, inhibits inflammatory reactions, and also acts as a tumor suppressor to impair the multiplication and invasion of tumor cells. These potentials provide new perspectives on the treatment of intestinal conditions, including inflammatory bowel disease (IBD) and its associated colorectal cancer (CRC). Moreover, FXR agonists on the market have certain organizational heterogeneity and may be used in combination with other drugs to achieve a greater therapeutic effect. This review summarizes current data on the role of FXR in bile acid metabolism, regulation of immune cells, and effects of the PTM of FXR. The functions of FXR in intestinal homeostasis and potential application in the treatment of IBD and CRC are discussed.
    Keywords:  Farnesoid X Receptor; colorectal cancer; immune cells; inflammatory bowel disease; post-translational modification; therapy
    DOI:  https://doi.org/10.3389/fphar.2022.1016836
  21. Dis Markers. 2022 ;2022 9025668
    CDX2 as a Predictive Biomarker Involved in Immunotherapy Response Suppresses Metastasis through EMT in Colorectal Cancer.
    Yun-Shuai Wang, Yu Kou, Ren-Tao Zhu, Bao-Wei Han, Chao-Hui Li, Huang-Jian Wang, Hui-Bin Wu, Tian-Ming Xia, Xiang-Ming Che.
       Background: Studies have confirmed that Caudal Type Homeobox 2 (CDX2) plays a tumor suppressor role in colorectal cancer (CRC) and as a prognostic and predictive marker for colorectal cancer. The epithelial to mesenchymal transition (EMT) is a transdifferentiation process, providing migratory and invasive properties to cancer cells during tumor progression. However, the role of CDX2 during the activation of EMT in CRC maintains controversial.
    Aim: To investigate whether CDX2 is associated with EMT in CRC.
    Methods: Forty-six CRC patients were included in the study. Expressions of CDX2, E-cadherin, and N-cadherin in all CRC patients were detected by IHC. ROC assays were applied to detect cut-off points for IHC scores to distinguish high and low expressions of CDX2 in 46 CRC samples. The prognostic value of CDX2 was statistically analyzed. MTT, Western blot, invasion, and migration assays in vitro were employed to explore the function of CDX2.
    Results: We observed that high expressions of CDX2 and E-cadherin as well as low expressions of N-cadherin were significantly correlated with favorable prognosis. The levels of CDX2 protein exhibited a positive associated with E-cadherin while negative correlation with N-cadherin. Then, the low expression of CDX2 and high expression of CA199 in combination are positively related with poor prognosis. Overexpression of CDX2 reduced expression of MMP-2 and diminished cell proliferation, invasion, and migration, while knockdown CDX2 enhanced MMP-2 expression and increased cell proliferation, invasion, and migration in HCT-116 cells. CDX2 was correlated with expression of EMT markers. Overexpression of CDX2 suppressed the EMT markers indicating that CDX2 suppresses CRC cell viability, invasion, and metastasis through inhibiting EMT. Finally, we found that the expression of CDX2 was negatively associated with Th1 cells, macrophages, Th2 cells, cytotoxic cells, T cells, and T helper cells.
    Conclusions: These results indicated CDX2 as prognostic biomarkers involved in immunotherapy response for CRC. CDX2 loss promotes metastasis in CRC through a CDX2-dependent mechanism.
    DOI:  https://doi.org/10.1155/2022/9025668
  22. Cancers (Basel). 2022 Oct 21. pii: 5160. [Epub ahead of print]14(20):
    Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies.
    Nannan Wang, Yuepeng Cao, Chengshuai Si, Peng Shao, Guoqing Su, Ke Wang, Jun Bao, Liu Yang.
      Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.
    Keywords:  ERBB2; HER2; colorectal cancer; targeted therapy
    DOI:  https://doi.org/10.3390/cancers14205160
  23. PLoS One. 2022 ;17(10): e0276195
    Generation of human colon organoids from healthy and inflammatory bowel disease mucosa.
    Isabella Dotti, Aida Mayorgas, Azucena Salas.
      Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases (IBD) of unknown cause characterized by a relapsing-remitting behavior. Growing evidence supports the idea that the epithelial barrier plays a central role in the pathogenesis of IBD as well as in its evolution over time, thus representing a potential target for novel therapeutic options. In the last decade, the introduction of 3D epithelial cultures from ex vivo-expanded intestinal adult stem cells (ASCs) has impacted our ability to study the function of the epithelium in several gastrointestinal disorders, including IBD. Here, we describe in detail a reproducible protocol to generate Matrigel-embedded epithelial organoids from ASCs of non-IBD and IBD donors using small colonic biopsies, including steps for its optimization. A slightly modified version of this protocol is also provided in case surgical samples are used. With this method, epithelial organoids can be expanded over several passages, thereby generating a large quantity of viable cells that can be used in multiple downstream analyses including genetic, transcriptional, proteomic and/or functional studies. In addition, 3D cultures generated using our protocol are suitable for the establishment of 2D cultures, which can model relevant cell-to-cell interactions that occur in IBD mucosa.
    DOI:  https://doi.org/10.1371/journal.pone.0276195
  24. BMC Med Genomics. 2022 10 21. 15(1): 221
    Role of a lipid metabolism-related lncRNA signature in risk stratification and immune microenvironment for colon cancer.
    Yaobin Lin, Yu Xiao, Shan Liu, Liang Hong, Lingdong Shao, Junxin Wu.
       BACKGROUND: Energy metabolism disorder, especially lipid metabolism disorder, is an important biological characteristic of colon cancer. This research sought to examine the association between lipid metabolism-related long non-coding RNAs (lncRNAs) and prognoses among colon cancer patients.
    METHODS: The transcriptome profile and clinical data of patients with colon cancer were retrieved from The Cancer Genome Atlas database. Using consensus clustering, cases were divided into two clusters and Kaplan-Meier analysis was executed to analyze differences in their prognoses. The gene set enrichment analysis (GSEA) was used to discover biological processes and signaling pathways. A lipid metabolism-related lncRNA prognostic model (lipid metabolism-LncRM) was created utilizing the least absolute shrinkage and selection operator (LASSO) regression. The tumor microenvironment was evaluated on the basis of the composition of immune and stromal cells.
    RESULTS: The patients in Cluster 2 were found to have a better prognosis and higher expression of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) relative to Cluster 1. The results of GSEA showed the enrichment of energy metabolism pathways in Cluster 2. LASSO regression was used to identify the five LncRNAs that were shown to be most substantially linked to patient prognosis. These were NSMCE1-DT, LINC02084, MYOSLID, LINC02428, and MRPS9-AS1. Receiver operating characteristic (ROC) curves and survival analysis illustrated that the lipid metabolism-LncRM had a significant prognostic value. Further analysis showed that high- and low-risk groups were significantly different in terms of clinical characteristics and immune cells infiltration.
    CONCLUSIONS: Lipid metabolism-related lncRNAs could predict the prognoses and tumor microenvironment of colon cancer and might be important biomarkers relevant to immunotherapy.
    Keywords:  Colon cancer; Lipid metabolism; Long non-coding RNAs; Prognosis; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12920-022-01369-8
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