bims-instec 2024-01-28 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2024–01–28
34 papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Navigating the Landscape of Intestinal Regeneration: A Spotlight on Quiescence Regulation and Fetal Reprogramming.
Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer.
Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling.
CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC.
Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs.
Intraepithelial Lymphocytes of the Intestine.
BRAF - a tumour-agnostic drug target with lineage-specific dependencies.
MEK-mediated CHPF2 phosphorylation promotes colorectal cancer cell proliferation and metastasis by activating NF-κB signaling.
Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression.
Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study.
Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment.
Intestinal Inflammation and Regeneration-Interdigitating Processes Controlled by Dietary Lipids in Inflammatory Bowel Disease.
Gut microbiome mediates ferroptosis resistance for colorectal cancer development.
Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.
Centrosomal Protein 55 (CEP55) Drives Immune Exclusion and Resistance to Immune Checkpoint Inhibitors in Colorectal Cancer.
Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation.
Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression.
Dietary iron is necessary to support proliferative regeneration following intestinal injury.
APC mutations disrupt β-catenin destruction complex condensates organized by Axin phase separation.
Carnosine helps cancer cells to evade immune surveillance by regulating intracellular pH.
Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53.
Metabolic heterogeneity in cancer.
New sights of immunometabolism and agent progress in colitis associated colorectal cancer.
Prognostic potential of MNX1-AS1 in chemotherapy of colorectal carcinoma.
The Role of Galectin3, Tubulinβ, and Maspin in Promoting Tumor Budding in Colorectal Carcinoma and Their Clinical Implication.
YAP1 expression in colorectal cancer confers the aggressive phenotypes via its target genes.
Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.
Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer.
Gastrointestinal perforation associated with bevacizumab in metastatic colorectal cancer.
Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.
PP2A drives the stemness in colorectal cancer cells by decreasing the Hippo signaling pathway.
The LKB1-TSSK1B axis controls YAP phosphorylation to regulate the Hippo-YAP pathway.
Exploring Potential Epigenetic Biomarkers for Colorectal Cancer Metastasis.
A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance.

Int J Stem Cells. 2024 Jan 25.

Navigating the Landscape of Intestinal Regeneration: A Spotlight on Quiescence Regulation and Fetal Reprogramming.

Su-Jeong Oh, Yoojin Seo, Hyung-Sik Kim.

  Tissue-specific adult stem cells are pivotal in maintaining tissue homeostasis, especially in the rapidly renewing intestinal epithelium. At the heart of this process are leucine-rich repeat-containing G protein-coupled receptor 5-expressing crypt base columnar cells (CBCs) that differentiate into various intestinal epithelial cells. However, while these CBCs are vital for tissue turnover, they are vulnerable to cytotoxic agents. Recent advances indicate that alternative stem cell sources drive the epithelial regeneration post-injury. Techniques like lineage tracing and single-cell RNA sequencing, combined with in vitro organoid systems, highlight the remarkable cellular adaptability of the intestinal epithelium during repair. These regenerative responses are mediated by the reactivation of conserved stem cells, predominantly quiescent stem cells and revival stem cells. With focus on these cells, this review unpacks underlying mechanisms governing intestinal regeneration and explores their potential clinical applications.

Keywords:  Adult stem cells; Cellular reprogramming; Intestinal stem cells; Regeneration

DOI:  https://doi.org/10.15283/ijsc23176
Cancers (Basel). 2024 Jan 18. pii: 412. [Epub ahead of print]16(2):

Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer.

Nadia Saoudi González, Javier Ros, Iosune Baraibar, Francesc Salvà, Marta Rodríguez-Castells, Adriana Alcaraz, Ariadna García, Josep Tabernero, Elena Élez.

  Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment.

Keywords:  BRAFV600; KRASG12C; cetuximab; colorectal cancer; personalized treatment

DOI:  https://doi.org/10.3390/cancers16020412
Front Pharmacol. 2023 ;14 1340401

Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling.

Najah Albadari, Yang Xie, Wei Li.

  In 2023, colorectal cancer (CRC) is the third most diagnosed malignancy and the third leading cause of cancer death worldwide. At the time of the initial visit, 20% of patients diagnosed with CRC have metastatic CRC (mCRC), and another 25% who present with localized disease will later develop metastases. Despite the improvement in response rates with various modulation strategies such as chemotherapy combined with targeted therapy, radiotherapy, and immunotherapy, the prognosis of mCRC is poor, with a 5-year survival rate of 14%, and the primary reason for treatment failure is believed to be the development of resistance to therapies. Herein, we provide an overview of the main mechanisms of resistance in mCRC and specifically highlight the role of drug transports, EGFR, and HGF/c-MET signaling pathway in mediating mCRC resistance, as well as discuss recent therapeutic approaches to reverse resistance caused by drug transports and resistance to anti-EGFR blockade caused by mutations in EGFR and alteration in HGF/c-MET signaling pathway.

Keywords:  ABC drug transporters; anti-EGFR; anti-MET; metastatic colorectal cancer; resistance; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3389/fphar.2023.1340401
Cancers (Basel). 2024 Jan 07. pii: 264. [Epub ahead of print]16(2):

CYP26A1 Links WNT and Retinoic Acid Signaling: A Target to Differentiate ALDH+ Stem Cells in APC-Mutant CRC.

Caroline O B Facey, Victoria O Hunsu, Chi Zhang, Brian Osmond, Lynn M Opdenaker, Bruce M Boman.

  APC mutation is the main driving mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between the WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induce wt-APC expression in APC-mutant CRC cells, and we assess the ability of all-trans retinoic acid (ATRA) to induce differentiation. We found that ATRA increased expression of the WNT target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, the RA and WNT pathways crosstalk to modulate CYP26A1, which metabolizes retinoids. Moreover, inducing wt-APC augments ATRA-induced cell differentiation by: (i) decreasing cell proliferation; (ii) suppressing ALDH1A1 expression; (iii) decreasing ALDH+ SCs; and (iv) increasing neuroendocrine cell differentiation. A novel CYP26A1-based network that links WNT and RA signaling was also identified by NanoString profiling/bioinformatics analysis. Furthermore, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably, in wt-APC-CRCs, decreased CYP26A1 improved patient survival. These findings have strong potential for clinical translation.

Keywords:  APC; CYP26A1; WNT; aldehyde dehydrogenase; cancer stem cells; colorectal cancer; neuroendocrine cells; retinoic acid

DOI:  https://doi.org/10.3390/cancers16020264
Exp Hematol Oncol. 2024 Jan 22. 13(1): 6

Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs.

Qi Zhao, Hong Zong, Pingping Zhu, Chang Su, Wenxue Tang, Zhenzhen Chen, Shuiling Jin.

  Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.

Keywords:  Colorectal cancer stem cells; Immune Cells; Immunotherapy; Targeting cancer stem cells; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s40164-024-00474-x
Annu Rev Immunol. 2024 Jan 26.

Intraepithelial Lymphocytes of the Intestine.

Ainsley Lockhart, Daniel Mucida, Angelina M Bilate.

The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-immunol-090222-100246
Nat Rev Clin Oncol. 2024 Jan 26.

BRAF - a tumour-agnostic drug target with lineage-specific dependencies.

Aphrothiti J Hanrahan, Ziyu Chen, Neal Rosen, David B Solit.

In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.

DOI: https://doi.org/10.1038/s41571-023-00852-0
Cancer Lett. 2024 Jan 21. pii: S0304-3835(24)00038-7. [Epub ahead of print] 216644

MEK-mediated CHPF2 phosphorylation promotes colorectal cancer cell proliferation and metastasis by activating NF-κB signaling.

Xiangqiong Wen, Jiale Qin, Xiang Zhang, Lvlan Ye, Youpeng Wang, Ranran Yang, Yuqin Di, Weiling He, Ziyang Wang.

  The cytokine tumor necrosis factor (TNF) plays a crucial role in the proliferation and metastasis of colorectal cancer (CRC) cells, but the underlying mechanisms remain poorly understood. Here, we report that chondroitin polymerizing factor 2 (CHPF2) promotes CRC cell proliferation and metastasis mediated by TNF, independently of its enzymatic activity. CHPF2 is highly expressed in CRC, and its elevated expression is associated with poor prognosis of CRC patients. Mechanistically, upon TNF stimulation, CHPF2 is phosphorylated at the T588 residue by MEK, enabling CHPF2 to interact with both TAK1 and IKKα. This interaction enhances the binding of TAK1 and IKKα, leading to increased phosphorylation of the IKK complex and activation of NF-κB signaling. As a result, the expression of early growth factors (EGR1) is upregulated to promote CRC cell proliferation and metastasis. In contrast, introduction of a phospho-deficient T588A mutation in CHPF2 weakened the interaction between CHPF2 and TAK1, thus impairing NF-κB signaling. CHPF2 T588A mutation reduced the ability of CHPF2 to promote the proliferation and metastasis of CRC in vitro and in vivo. Furthermore, the NF-κB RELA subunit promotes CHPF2 expression, further amplifying TNF-induced NF-κB signaling activation. These findings identify a moonlighting function of CHPF2 in promoting tumor cell proliferation and metastasis and provide insights into the mechanism by which CHPF2 amplifies TNF-mediated NF-κB signaling activation. Our study provides a molecular basic for the development of therapeutic strategies for CRC treatment.

Keywords:  CHPF2 phosphorylation; Colorectal cancer proliferation and metastasis; MEK kinase; NF-κB signaling; TNF

DOI:  https://doi.org/10.1016/j.canlet.2024.216644
JCI Insight. 2024 Jan 23. pii: e170428. [Epub ahead of print]9(2):

Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression.

Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu.

  Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Keywords:  Colorectal cancer; Endocrinology; Gastroenterology

DOI:  https://doi.org/10.1172/jci.insight.170428
Curr Oncol. 2024 Jan 03. 31(1): 274-295

Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study.

Juan Pablo Cayún, Leslie Carol Cerpa, Alicia Colombo, Dante Daniel Cáceres, José Luis Leal, Felipe Reyes, Carolina Gutiérrez-Cáceres, Susan Calfunao, Nelson Miguel Varela, Luis Abel Quiñones.

  Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.

Keywords:  biomarkers; colorectal cancer; pharmacogenomics

DOI:  https://doi.org/10.3390/curroncol31010018
Cell Metab. 2024 Jan 17. pii: S1550-4131(23)00477-1. [Epub ahead of print]

Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment.

Wei Wei, Yali Liu, Yuanlong Hou, Shuqi Cao, Zhuo Chen, Youying Zhang, Xiaoying Cai, Qingyuan Yan, Ziguang Li, Yonggui Yuan, Guangji Wang, Xiao Zheng, Haiping Hao.

  The brain and gut are intricately connected and respond to various stimuli. Stress-induced brain-gut communication is implicated in the pathogenesis and relapse of gut disorders. The mechanism that relays psychological stress to the intestinal epithelium, resulting in maladaptation, remains poorly understood. Here, we describe a stress-responsive brain-to-gut metabolic axis that impairs intestinal stem cell (ISC) lineage commitment. Psychological stress-triggered sympathetic output enriches gut commensal Lactobacillus murinus, increasing the production of indole-3-acetate (IAA), which contributes to a transferrable loss of intestinal secretory cells. Bacterial IAA disrupts ISC mitochondrial bioenergetics and thereby prevents secretory lineage commitment in a cell-intrinsic manner. Oral α-ketoglutarate supplementation bolsters ISC differentiation and confers resilience to stress-triggered intestinal epithelial injury. We confirm that fecal IAA is higher in patients with mental distress and is correlated with gut dysfunction. These findings uncover a microbe-mediated brain-gut pathway that could be therapeutically targeted for stress-driven gut-brain comorbidities.

Keywords:  Lactobacillus; brain-body communication; gut-brain axis; inflammatory bowel disease; intestinal stem cell; microbial metabolism; mitochondrial respiration; psychological stress; tryptophan metabolites

DOI:  https://doi.org/10.1016/j.cmet.2023.12.026
Int J Mol Sci. 2024 Jan 21. pii: 1311. [Epub ahead of print]25(2):

Intestinal Inflammation and Regeneration-Interdigitating Processes Controlled by Dietary Lipids in Inflammatory Bowel Disease.

Soon Jae Kwon, Muhammad Sohaib Khan, Sang Geon Kim.

  Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a disease of chronic inflammatory conditions of the intestinal tract due to disturbance of the inflammation and immune system. Symptoms of IBD include abdominal pain, diarrhea, bleeding, reduced weight, and fatigue. In IBD, the immune system attacks the intestinal tract's inner wall, causing chronic inflammation and tissue damage. In particular, interlukin-6 and interlukin-17 act on immune cells, including T cells and macrophages, to amplify the immune responses so that tissue damage and morphological changes occur. Of note, excessive calorie intake and obesity also affect the immune system due to inflammation caused by lipotoxicity and changes in lipids supply. Similarly, individuals with IBD have alterations in liver function after sustained high-fat diet feeding. In addition, excess dietary fat intake, along with alterations in primary and secondary bile acids in the colon, can affect the onset and progression of IBD because inflammatory cytokines contribute to insulin resistance; the factors include the release of inflammatory cytokines, oxidative stress, and changes in intestinal microflora, which may also contribute to disease progression. However, interfering with de novo fatty acid synthase by deleting the enzyme acetyl-CoA-carboxylase 1 in intestinal epithelial cells (IEC) leads to the deficiency of epithelial crypt structures and tissue regeneration, which seems to be due to Lgr5+ intestinal stem cell function. Thus, conflicting reports exist regarding high-fat diet effects on IBD animal models. This review will focus on the pathological basis of the link between dietary lipids intake and IBD and will cover the currently available pharmacological approaches.

Keywords:  IBD; IECs; inflammation; lipid intake; stem cells

DOI:  https://doi.org/10.3390/ijms25021311
Cancer Res. 2024 Jan 26.

Gut microbiome mediates ferroptosis resistance for colorectal cancer development.

Ruoxi Zhang, Rui Kang, Daolin Tang.

Colorectal cancer (CRC) is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in CRC development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes CRC by inhibiting ferroptosis, a type of non-apoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10) by apoptosis inducing factor mitochondria associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2, or ALDH1A3 reverses the inhibitory effect of IDA on ferroptosis and IDA-mediated tumor growth. Significantly, P. anaerobius is enriched in CRC patients, and supplementing IDA or P. anaerobius accelerates CRC progression in spontaneous or orthotopic mouse models. Taken together, these findings suggest that targeting P. anaerobius-mediated ferroptosis resistance emerges as a promising strategy to combat CRC development.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0275
Nat Commun. 2024 Jan 25. 15(1): 749

Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.

Nikolaos M R Lykoskoufis, Evarist Planet, Halit Ongen, Didier Trono, Emmanouil T Dermitzakis.

Transposable elements (TEs) are prevalent repeats in the human genome, play a significant role in the regulome, and their disruption can contribute to tumorigenesis. However, TE influence on gene expression in cancer remains unclear. Here, we analyze 275 normal colon and 276 colorectal cancer samples from the SYSCOL cohort, discovering 10,231 and 5,199 TE-expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively, of which 376 are colorectal cancer specific eQTLs, likely due to methylation changes. Tumor-specific TE-eQTLs show greater enrichment of transcription factors, compared to shared TE-eQTLs suggesting specific regulation of their expression in tumor. Bayesian networks reveal 1,766 TEs as mediators of genetic effects, altering the expression of 1,558 genes, including 55 known cancer driver genes and show that tumor-specific TE-eQTLs trigger the driver capability of TEs. These insights expand our knowledge of cancer drivers, deepening our understanding of tumorigenesis and presenting potential avenues for therapeutic interventions.

DOI: https://doi.org/10.1038/s41467-023-42405-0
Vaccines (Basel). 2024 Jan 08. pii: 63. [Epub ahead of print]12(1):

Centrosomal Protein 55 (CEP55) Drives Immune Exclusion and Resistance to Immune Checkpoint Inhibitors in Colorectal Cancer.

Dechen Wangmo, Travis J Gates, Xianda Zhao, Ruping Sun, Subbaya Subramanian.

  Colorectal cancer (CRC) currently ranks as the third most common cancer in the United States, and its incidence is on the rise, especially among younger individuals. Despite the remarkable success of immune checkpoint inhibitors (ICIs) in various cancers, most CRC patients fail to respond due to intrinsic resistance mechanisms. While microsatellite instability-high phenotypes serve as a reliable positive predictive biomarker for ICI treatment, the majority of CRC patients with microsatellite-stable (MSS) tumors remain ineligible for this therapeutic approach. In this study, we investigated the role of centrosomal protein 55 (CEP55) in shaping the tumor immune microenvironment in CRC. CEP55 is overexpressed in multiple cancer types and was shown to promote tumorigenesis by upregulating the PI3K/AKT pathway. Our data revealed that elevated CEP55 expression in CRC was associated with reduced T cell infiltration, contributing to immune exclusion. As CRC tumors progressed, CEP55 expression increased alongside sequential mutations in crucial driver genes (APC, KRAS, TP53, and SMAD4), indicating its involvement in tumor progression. CEP55 knockout significantly impaired tumor growth in vitro and in vivo, suggesting that CEP55 plays a crucial role in tumorigenesis. Furthermore, the CEP55 knockout increased CD8+ T cell infiltration and granzyme B production, indicating improved anti-tumor immunity. Additionally, we observed reduced regulatory T cell infiltration in CEP55 knockout tumors, suggesting diminished immune suppression. Most significantly, CEP55 knockout tumors demonstrated enhanced responsiveness to immune checkpoint inhibition in a clinically relevant orthotopic CRC model. Treatment with anti-PD1 significantly reduced tumor growth in CEP55 knockout tumors compared to control tumors, suggesting that inhibiting CEP55 could improve the efficacy of ICIs. Collectively, our study underscores the crucial role of CEP55 in driving immune exclusion and resistance to ICIs in CRC. Targeting CEP55 emerges as a promising therapeutic strategy to sensitize CRC to immune checkpoint inhibition, thereby improving survival outcomes for CRC patients.

Keywords:  CEP55; T cells; colorectal cancer; immune checkpoint inhibition; immune regulation

DOI:  https://doi.org/10.3390/vaccines12010063
Cell Death Discov. 2024 Jan 23. 10(1): 41

Non-alcoholic fatty liver disease promotes liver metastasis of colorectal cancer via fatty acid synthase dependent EGFR palmitoylation.

Chi Zhang, Yue Zhang, Yan Dong, Ruiyang Zi, Yijie Wang, Yanrong Chen, Chengxiang Liu, Junyi Wang, Xuesong Wang, Jianjun Li, Houjie Liang, Juanjuan Ou.

Liver metastasis is the major reason for most of colorectal cancer (CRC) related deaths. Accumulating evidence indicates that CRC patients with non-alcoholic fatty liver disease (NAFLD) are at a greater risk of developing liver metastasis. With the growing prevalence of NAFLD, a better understanding of the molecular mechanism in NAFLD-driven CRC liver metastasis is needed. In this study, we demonstrated that NAFLD facilitated CRC liver metastasis as a metabolic disorder and promoted the stemness of metastatic CRC cells for their colonization and outgrowth in hepatic niches. Metabolically, the lipid-rich microenvironment in NAFLD activated de novo palmitate biosynthesis in metastatic CRC cells via upregulating fatty acid synthase (FASN). Moreover, increased intracellular palmitate bioavailability promoted EGFR palmitoylation to enhance its protein stability and plasma membrane localization. Furthermore, we demonstrated that the FDA-approved FASN inhibitor orlistat could reduce NAFLD-activated endogenous palmitate production, thus inhibiting palmitoylation of EGFR to suppress CRC cell stemness and restrict liver metastasis in synergy with conventional chemotherapy. These findings reveal that the NAFLD metabolic microenvironment boosts endogenous palmitate biosynthesis in metastatic CRC cells and promotes cell stemness via EGFR palmitoylation, and FASN inhibitor orlistat could be a candidate adjuvant drug to suppress liver metastasis in CRC patients with NAFLD.

DOI: https://doi.org/10.1038/s41420-023-01770-x
Cell Death Dis. 2024 Jan 24. 15(1): 85

Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression.

Kang Lin, Yun Zhao, Yuqi Tang, Ying Chen, Moubin Lin, Luwei He.

The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM) remodeling transforms the tumor microenvironment. Collagen I, a major with ECM component is highly expressed in colorectal tumors with infiltrative growth. Although oxysterol binding protein (OSBP)-related proteins accommodate tumorigenesis, OSBPL2, which is usually involved in deafness, is not associated with CRC progression. Therefore, we aimed to investigate the pathological function of OSBPL2 and identify the molecular link between ECM-Collagen I and OSBPL2 in CRC to facilitate the development of new treatments for CRC. OSBPL2 predicted a favorable prognosis in stage IV CRC and substantially repressed Collagen I-induced focal adhesion, migration, and invasion. The reduction of OSBPL2 activated ERK signaling through the VCAN/AREG/EREG axis during CRC growth, while relying on PARP1 via ZEB1 in CRC metastasis. OSBPL2 defect supported colorectal tumor growth and metastasis, which were suppressed by the ERK and PARP1 inhibitors SCH772984 and AG14361, respectively. Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2Low CRC, which could contribute to further development of targeted CRC treatment.

DOI: https://doi.org/10.1038/s41419-024-06468-1
J Nutr. 2024 Jan 19. pii: S0022-3166(24)00032-4. [Epub ahead of print]

Dietary iron is necessary to support proliferative regeneration following intestinal injury.

Wesley Huang, Nupur K Das, Megan D Radyk, Theresa Keeley, Miguel Quiros, Chesta Jain, Marwa O El-Derany, Thaarini Swaminathan, Sofia Dziechciarz, Joel K Greenson, Asma Nusrat, Linda C Samuelson, Yatrik M Shah.

   BACKGROUND: Tissue repair and regeneration in the gastrointestinal system is crucial for maintaining homeostasis, with the process relying on intricate cellular interactions and affected by micro and macro-nutrients. Iron, essential for various biological functions, plays a dual role in tissue healing by potentially causing oxidative damage and participating in anti-inflammatory mechanisms, underscoring its complex relationship with inflammation and tissue repair.
OBJECTIVE: The study aimed to elucidate the role of low dietary iron in gastrointestinal tissue repair.
METHODS: We utilized quantitative iron measurements to assess iron levels in inflamed regions of ulcerative colitis and Crohn's disease patients. Additionally, three mouse models of gastrointestinal injury/repair (dextran sulfate sodium-induced colitis, radiation injury, and wound biopsy) were used to assess the effects of low dietary iron on tissue repair.
RESULTS: We found that levels of iron in inflamed regions of both ulcerative colitis and Crohn's disease patients are elevated. Similarly, during gastrointestinal repair, iron levels were found to be heightened, specifically in intestinal epithelial cells across the three injury/repair models. Mice on a low iron diet showed compromised tissue repair with reduced proliferation. In standard diet, epithelial cells and the stem cell compartment maintain adequate iron stores. However, during a period of iron deficiency, epithelial cells exhaust their iron reserves while the stem cell compartment maintain their iron pools. During injury, when the stem compartment in disrupted, low iron levels impair proliferation and compromise repair mechanisms.
CONCLUSIONS: Low dietary iron impairs intestinal repair through compromising the ability of epithelial cells to aid in intestinal proliferation.

Keywords:  intestinal injury; intestinal proliferation; iron; tissue repair; wound healing

DOI:  https://doi.org/10.1016/j.tjnut.2024.01.013
Cell Mol Life Sci. 2024 Jan 27. 81(1): 57

APC mutations disrupt β-catenin destruction complex condensates organized by Axin phase separation.

Dan Zhang, Qi-Qi Ni, Shu-Yang Wang, Wen-Feng He, Ze-Xuan Hong, Hui-Ye Liu, Xiao-Hong Chen, Li-Jie Chen, Fang-Yi Han, Ling-Jie Zhang, Xiao-Ming Li, Yan-Qing Ding, Hong-Li Jiao, Ya-Ping Ye.

  The Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the β-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of β-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the β-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3β and CK1α were unsuccessfully recruited, preventing β-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of β-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.

Keywords:  APC mutations; Axin; Colorectal cancer; Destruction complex; Nuclear transport; Phase separation; Wnt/β-catenin signaling pathway

DOI:  https://doi.org/10.1007/s00018-023-05068-0
Nat Immunol. 2024 Jan 25.

Carnosine helps cancer cells to evade immune surveillance by regulating intracellular pH.

DOI: https://doi.org/10.1038/s41590-023-01740-6
Res Sq. 2024 Jan 10. pii: rs.3.rs-3782833. [Epub ahead of print]

Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53.

Hua Lu, Zhihui Tan, Hyunmin Ko, Parnia Naji, Rong Zhu, Jieqiong Wang, Shibo Huang, Yi-Wei Zhang, Shelya Zeng.

Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that exhibits divergent roles in various cancer types (oncogenic and anti-oncogenic). This study investigates the interaction of TRIM26 with the tumor suppressor protein p53 in colorectal cancer (CRC) cells by performing a comprehensive set of biochemical, cell-based assays, and xenograft experiments. As a result, we found that overexpression of TRIM26 significantly enhances CRC cell proliferation and colony formation, while knockdown of TRIM26 suppresses these processes. Xenograft experiments further validated the tumor-promoting role of TRIM26 in CRC. Supporting this is that TRIM26 is highly expressed in human CRC tissues as revealed by our analysis of the TCGA database. Biochemically, TRIM26 directly bound to the C-terminus of p53 and facilitated its ubiquitination, resulting in proteolytic degradation and attenuated p53 activity independently of MDM2. Also, TRIM26 increased the MDM2-mediated ubiquitination of p53 by binding to MDM2's C-terminus. This study uncovers the oncogenic potential of TRIM26 in CRC by inhibiting p53 function. Through its ubiquitin ligase activity, TRIM26 destabilizes p53, consequently promoting CRC cell proliferation and tumor growth. These findings shed light on the complex involvement of TRIM26 in cancer and identify this ubiquitin ligase as a potential therapeutic target for future development of CRC treatment.

DOI: https://doi.org/10.21203/rs.3.rs-3782833/v1
Nat Metab. 2024 Jan 24.

Metabolic heterogeneity in cancer.

Margherita Demicco, Xiao-Zheng Liu, Katharina Leithner, Sarah-Maria Fendt.

Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumour metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterisation of metabolic heterogeneity in tumours. In addition to the metabolic heterogeneity observed in primary tumours, metabolic heterogeneity temporally evolves along with tumour progression. In this Review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment.

DOI: https://doi.org/10.1038/s42255-023-00963-z
Front Pharmacol. 2023 ;14 1303913

New sights of immunometabolism and agent progress in colitis associated colorectal cancer.

Jingyue Zhang, Chaoyue Chen, Wei Yan, Yu Fu.

  Colitis associated colorectal cancer is a disease with a high incidence and complex course that develops from chronic inflammation and deteriorates after various immune responses and inflammation-induced attacks. Colitis associated colorectal cancer has the characteristics of both immune diseases and cancer, and the similarity of treatment models contributes to the similar treatment dilemma. Immunometabolism contributes to the basis of life and is the core of many immune diseases. Manipulating metabolic signal transduction can be an effective way to control the immune process, which is expected to become a new target for colitis associated colorectal cancer therapy. Immune cells participate in the whole process of colitis associated colorectal cancer development by transforming their functional condition via changing their metabolic ways, such as glucose, lipid, and amino acid metabolism. The same immune and metabolic processes may play different roles in inflammation, dysplasia, and carcinoma, so anti-inflammation agents, immunomodulators, and agents targeting special metabolism should be used in combination to prevent and inhibit the development of colitis associated colorectal cancer.

Keywords:  colitis associated colorectal cancer; immune adaption; immunometabolism; inflammation; metabolic reprogramming; metabolites; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2023.1303913
Cell Mol Biol (Noisy-le-grand). 2023 Dec 20. 69(14): 243-247

Prognostic potential of MNX1-AS1 in chemotherapy of colorectal carcinoma.

Guangjun Zhong, Ming Zhou, Zhaojun Wang, Wansen Zhu.

To clarify the role of MNX1-AS1 in 5-FU resistance of Colorectal carcinoma (CRC). Relative levels of MNX1-AS1 in CRC and paracancerous tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Recruited CRC patients were treated by 5-FU-based FOLFOX chemotherapy, and they were divided to effective group and non-effective group according to the therapeutic efficacy, followed by comparison of their differences in clinical indicators. Influences of MNX1-AS1 on clinical features of CRC were analyzed. In addition, in vitro level of MNX1-AS1 in 5-FU-resistant HCT-8 cells and their parental cells was detected. After knockdown of MNX1-AS1 in HCT-8/5-FU cells, viability change was evaluated by cell counting kit-8 (CCK-8) assay. At last, regulatory effects of MNX1-AS1 on expression levels of ABC family genes were detected. MNX1-AS1 was upregulated in CRC tissues than paracancerous ones, and its level was higher in 5-FU-resistant CRC cases in comparison to 5-FU-sensitive cases. MNX1-AS1 level was linked to tumor size, tumor differentiation, depth of invasion, TNM staging and lymphatic metastasis in CRC. Notably, TNM staging, depth of invasion and lymphatic metastasis could affect the efficacy of FOLFOX chemotherapy in CRC patients. Knockdown of MNX1-AS1 reduced viability in HCT-8/5-FU cells, and downregulated ABCA1, ABCB1, ABCC1, ABCG1 and ABCG2. MNX1-AS1 triggers 5-FU resistance in CRC cells. Knockdown of MNXK1-AS1 is conductive to the well response to FOLFOX chemotherapy in CRC patients.

DOI: https://doi.org/10.14715/cmb/2023.69.14.41
Appl Immunohistochem Mol Morphol. 2024 Jan 22.

The Role of Galectin3, Tubulinβ, and Maspin in Promoting Tumor Budding in Colorectal Carcinoma and Their Clinical Implication.

Noha Elkady, Dina M Allam.

Colorectal cancer (CRC) is a leading cause of death worldwide. Despite the advances in surgical and therapeutic management, tumor metastases and poor prognosis are still major problems. Tumor budding is a relevant prognostic factor in CRC, and it can predict tumor metastasis. Galectin3 is responsible for the development and progression of many cancers through the regulation of cell-cell/cell-matrix interactions and tumor cell invasion. Tubulin is a microtubule protein, and maspin is a serine protease inhibitor; both induce tumor cell invasion through the stimulation of epithelial-mesenchymal transition. This study aims to evaluate the relationship between the expression of galecin3, tubulinβ, and maspin in CRC and clinicopathological features, including tumor budding, their prognostic roles, and clinical implications using immunohistochemistry. Galectin3, tubulinβ, and maspin were detected in tumor cells in 95%, 65%, and 87.5% of cases and in stromal cells in 28.8%, 40%, and 0% of cases. High expression of galectin3 and tubulinβ expression either in tumor cells or stroma was significantly associated with aggressive tumor features such as lymph node metastasis, lymphovascular invasion, tumor budding, and advanced tumor stage. The nucleocytoplasmic expression of maspin in tumor cells showed a significant association with deeper tumor invasion, lymph node metastasis, tumor budding, and advanced tumor stage. Significant associations were found between high galectin3 tumor cell expression and nucleocytoplasmic maspin and shorter survival. High expression of galectin3, tubulinβ, and nucleocytoplasmic maspin were significantly associated with aggressive tumor features such as tumor invasion, metastasis, high tumor budding, and short survival in CRC. They could be used as biomarkers for tumor budding and tumor aggressiveness in CRC and may be considered for future target therapy.

DOI: https://doi.org/10.1097/PAI.0000000000001183
Cell Cycle. 2024 Jan 23. 1-9

YAP1 expression in colorectal cancer confers the aggressive phenotypes via its target genes.

Haoyuan Chen, Yangyang Shang, Xia Li, Rongquan Wang.

  Yes-associated protein1 (YAP1), a downstream effector of the Hippo pathway, is over-expressed in several types of malignancies. We analyzed retrospectively the TCGA database using 447 colorectal cancer (CRC) samples to determine the correlation between YAP1 expression level and CRC patient prognosis. YAP1-enforced expressed CRC cell lines were constructed using the lentivirus particles containing a YAP1 insert. YAP1 was highly expressed in CRC cancerous tissues and is associated with distant metastasis of CRC patients. Kaplan - Meier analysis indicated that CRC patients with a higher YAP1 expression group (n = 104) had worse disease-free survival (DFS) and overall survival (OS) than lower YAP1 expression group (n = 343) (p = 0.008 and p = 0.022). Univariate and multivariate analysis indicated that the elevated YAP1 expression predicted the aggressive phenotype and was an independent indicator for OS and DFS of CRC patients. YAP1 over-expression in CRC cells enhanced their migration and invasion significantly which can be reversed by AXL, CTGF, or CYR61 interference. The study suggested that YAP1 affected the prognosis of CRC patients and controlled the abilities of invasion and migration of CRC cells via its target genes AXL, CTGF, and CYR61.

Keywords:  YAP1; colorectal cancer; hippo signaling; migration; prognosis; survival

DOI:  https://doi.org/10.1080/15384101.2024.2309017
Res Sq. 2024 Jan 08. pii: rs.3.rs-3837925. [Epub ahead of print]

Glutathione peroxidase 4 suppresses manganese-dependent oxidative stress to reduce colorectal tumorigenesis.

Xiang Xue, Zhaoli Liu, Yanshan Liang, Young-Yon Kwon, Rui Liu, David Martin, Sheng Hui.

The role of glutathione peroxidase 4 (GPX4) in ferroptosis and various cancers is well-established; however, its specific contribution to colorectal cancer has been unclear. Surprisingly, in a genetic mouse model of colon tumors, the deletion of GPX4 specifically in colon epithelial cells increased tumor burden but decreased oxidized glutathione. Notably, this specific GPX4 deletion did not enhance susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice with varied iron diets but showed vulnerability in mice with a vitamin E-deficient diet. Additionally, a high manganese diet heightened susceptibility, while a low manganese diet reduced DSS-induced colitis in colon epithelial-specific GPX4-deficient mice. Strikingly, the low manganese diet also significantly reduced colorectal cancer formation in both colon epithelial-specific GPX4-deficient and wildtype mice. Mechanistically, antioxidant proteins, especially manganese-dependent superoxide dismutase (MnSOD or SOD2), correlated with disease severity. Treatment with tempol, a superoxide dismutase mimetic radical scavenger, suppressed GPX4 deficiency-induced colorectal tumors. In conclusion, the study elucidates the critical role of GPX4 in inhibiting colorectal cancer progression by regulating oxidative stress in a manganese-dependent manner. The findings underscore the intricate interactions between GPX4, dietary factors, and their collective influence on colorectal cancer development, providing potential insights for personalized therapeutic strategies.

DOI: https://doi.org/10.21203/rs.3.rs-3837925/v1
Cancer Sci. 2024 Jan 26.

Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer.

Yong Zhang, Lu Li, Feifei Chu, Huili Wu, Xingguo Xiao, Jianping Ye, Kunkun Li.

  Advanced colorectal cancer (CRC) is characterized by a high recurrence and metastasis rate, which is the primary cause of patient mortality. Unfortunately, effective anti-cancer drugs for CRC are still lacking in clinical practice. We screened FDA-approved drugs by utilizing targeted organoid sequencing data and found that the antifungal drug itraconazole had a potential therapeutic effect on CRC tumors. However, the effect and mechanism of itraconazole on CRC tumors have not been investigated. A cell line-derived xenograft model in tumor-bearing mice was established and single-cell RNA sequencing was performed on tumor samples from four mice with or without itraconazole treatment. The proportion of cell populations and gene expression profiles was significantly different between the two groups. We found that itraconazole could inhibit tumor growth and glycolysis. We revealed that CEBPB was a new target for itraconazole, and that silencing CEBPB could repress CRC glycolysis and tumor growth by inhibiting ENO1 expression. Clinical analysis showed that CEBPB expression was obviously elevated in CRC patients, and was associated with poor survival. In summary, itraconazole treatment remodeled cell composition and gene expression profiles. Itraconazole inhibited cell glycolysis and tumor growth via the CEBPB-ENO1 axis. In this study, we illustrate a new energy metabolism mechanism for itraconazole on tumor growth in CRC that will provide a theoretical basis for CRC targeting/combination therapy.

Keywords:  CEBPB; colorectal cancer; glycolysis; itraconazole; single-cell RNA sequencing

DOI:  https://doi.org/10.1111/cas.16082
Cancer Rep (Hoboken). 2024 Jan 22. e1952

Gastrointestinal perforation associated with bevacizumab in metastatic colorectal cancer.

Kunpeng Fang, Jie Wang, Jianyong Yuan, Chengjun Sui, Jiajun Zhi, Yong Xia, Minmin Sun.

   OBJECTIVE: To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab.
METHODS: We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation.
RESULTS: All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab.
CONCLUSIONS: Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation.

Keywords:  adverse reactions; bevacizumab; colorectal cancer; gastrointestinal perforation

DOI:  https://doi.org/10.1002/cnr2.1952
bioRxiv. 2024 Jan 09. pii: 2024.01.09.574746. [Epub ahead of print]

Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.

Pratik N P Singh, Wei Gu, Shariq Madha, Allen W Lynch, Paloma Cejas, Ruiyang He, Swarnabh Bhattacharya, Miguel M Gomez, Matthew G Oser, Myles Brown, Henry W Long, Clifford A Meyer, Qiao Zhou, Ramesh A Shivdasani.

Enteroendocrine cells (EECs), which secrete serotonin (enterochromaffin cells, EC) or a dominant peptide hormone, serve vital physiologic functions. As with any adult human lineage, the basis for terminal cell diversity remains obscure. We replicated human EEC differentiation in vitro , mapped transcriptional and chromatin dynamics that culminate in discrete cell types, and studied abundant EEC precursors expressing selected transcription factors (TFs) and gene programs. Before expressing the pre-terminal factor NEUROD1, non-replicating precursors oscillated between epigenetically similar but transcriptionally distinct ASCL1 + and HES6 hi cell states. Loss of either factor substantially accelerated EEC differentiation and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and hormone-producing cell features. Expressed late in EEC differentiation, the latter TFs mainly bind cis -elements that are accessible in undifferentiated stem cells and tailor the subsequent expression of TF combinations that specify EEC types. Thus, TF oscillations retard EEC maturation to enable accurate EEC diversification.

DOI: https://doi.org/10.1101/2024.01.09.574746
Cell Mol Biol (Noisy-le-grand). 2023 Dec 20. 69(14): 114-120

PP2A drives the stemness in colorectal cancer cells by decreasing the Hippo signaling pathway.

Meng Wang, Ting Chen, Jie Zhang, Xing Wen.

Colorectal cancer (CRC) is one of the most prevalent malignancies. Accumulating evidence suggests that Hippo signaling pathway is a crucial signaling pathway that regulates stemness in multiple cancers, including CRC. Given that, the therapeutics targeting the Hippo pathway are of great interest. At the same time, previous studies have reported that PP2A regulates the Hippo pathway in tumorigenesis. In this study, we uncover the role of PP2A in vitro and in vivo and the interaction between PP2A and Hippo signaling pathway in CRC stemness. We investigate the molecular mechanism of PP2A-mediated Hippo pathway in CRC progression from the aspect of cell stemness. Furthermore, we explore the transcription factor of PP2A in CRC. In view of circRNA's regulation of cancer-related signaling pathways in CRC, we also study the association between PP2A-mediated Hippo pathway and the CRC-related circRNA (hsa-circ-001680) confirmed in previous studies. Of note, we demonstrate how hsa-circ-001680 regulates PP2A expression. The effect of hsa-circ-001680 on PP2A stability is investigated as well. In conclusion, the study demonstrates the mechanism of PP2A-mediated pathway on CRC stemness, which may provide new sights for the treatment of CRC.

DOI: https://doi.org/10.14715/cmb/2023.69.14.18
Cell Death Dis. 2024 01 20. 15(1): 76

The LKB1-TSSK1B axis controls YAP phosphorylation to regulate the Hippo-YAP pathway.

Cho-Long Kim, Su-Bin Lim, Sue-Hee Choi, Dong Hyun Kim, Ye Eun Sim, Eun-Hye Jo, Keeeun Kim, Keesook Lee, Hee-Sae Park, Su Bin Lim, Li-Jung Kang, Han-Sol Jeong, Youngsoo Lee, Carsten G Hansen, Jung-Soon Mo.

The Hippo pathway's main effector, Yes-associated protein (YAP), plays a crucial role in tumorigenesis as a transcriptional coactivator. YAP's phosphorylation by core upstream components of the Hippo pathway, such as mammalian Ste20 kinase 1/2 (MST1/2), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), and their substrate, large tumor suppressor 1/2 (LATS1/2), influences YAP's subcellular localization, stability, and transcriptional activity. However, recent research suggests the existence of alternative pathways that phosphorylate YAP, independent of these core upstream Hippo pathway components, raising questions about additional means to inactivate YAP. In this study, we present evidence demonstrating that TSSK1B, a calcium/calmodulin-dependent protein kinase (CAMK) superfamily member, is a negative regulator of YAP, suppressing cellular proliferation and oncogenic transformation. Mechanistically, TSSK1B inhibits YAP through two distinct pathways. Firstly, the LKB1-TSSK1B axis directly phosphorylates YAP at Ser94, inhibiting the YAP-TEAD complex's formation and suppressing its target genes' expression. Secondly, the TSSK1B-LATS1/2 axis inhibits YAP via phosphorylation at Ser127. Our findings reveal the involvement of TSSK1B-mediated molecular mechanisms in the Hippo-YAP pathway, emphasizing the importance of multilevel regulation in critical cellular decision-making processes.

DOI: https://doi.org/10.1038/s41419-024-06465-4
Int J Mol Sci. 2024 Jan 10. pii: 874. [Epub ahead of print]25(2):

Exploring Potential Epigenetic Biomarkers for Colorectal Cancer Metastasis.

Priyadarshana Ajithkumar, Sai Shyam Vasantharajan, Sharon Pattison, John L McCall, Euan J Rodger, Aniruddha Chatterjee.

  Metastatic progression is a complex, multistep process and the leading cause of cancer mortality. There is growing evidence that emphasises the significance of epigenetic modification, specifically DNA methylation and histone modifications, in influencing colorectal (CRC) metastasis. Epigenetic modifications influence the expression of genes involved in various cellular processes, including the pathways associated with metastasis. These modifications could contribute to metastatic progression by enhancing oncogenes and silencing tumour suppressor genes. Moreover, specific epigenetic alterations enable cancer cells to acquire invasive and metastatic characteristics by altering cell adhesion, migration, and invasion-related pathways. Exploring the involvement of DNA methylation and histone modification is crucial for identifying biomarkers that impact cancer prediction for metastasis in CRC. This review provides a summary of the potential epigenetic biomarkers associated with metastasis in CRC, particularly DNA methylation and histone modifications, and examines the pathways associated with these biomarkers.

Keywords:  DNA methylation; biomarkers; colorectal cancer; epigenetics; histone modification; liver; lymph node; metastasis

DOI:  https://doi.org/10.3390/ijms25020874
Cell Biochem Funct. 2024 Jan;42(1): e3906

A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance.

Anggraeni E Kusumaningrum, Sarce Makaba, Eyhab Ali, Mandeep Singh, Mohammed N Fenjan, Irodakhon Rasulova, Neeti Misra, Sada G Al-Musawi, Ali Alsalamy.

  The majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer-related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting-edge targeted medications are now the go-to option for customized and all-encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC-targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well-known due to developments in precision diagnostics and the extensive use of second-generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI-H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast-growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.

Keywords:  CRC; angiogenesis; drug resistance; metastasis; personalized medicine; tissue-based biomarkers

DOI:  https://doi.org/10.1002/cbf.3906