The inflammatory pathogenesis of colorectal cancer

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(10), P. 653 - 667

Published: April 28, 2021

Language: Английский

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Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(2), P. 168 - 184.e13

Published: Feb. 1, 2022

Standard cancer therapy targets tumor cells without considering possible damage on the microenvironment that could impair response. In rectal patients we find inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy Employing a murine model or patient-derived organoids and primary stroma cells, show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes toward phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results resistance disease progression. Consistently, IL-1 inhibition, prevention of senolytic sensitizes mice while lower receptor antagonist serum levels correlate prognosis. Collectively, unravel critical role for identify signaling as an attractive target stroma-repolarization senescence.

Language: Английский

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Fibroblast pathology in inflammatory diseases

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(20)

Published: Oct. 14, 2021

Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and bowel disease, fibroblasts take on different roles (a) themselves (b) in recruiting leukocytes, driving angiogenesis, enabling chronic inflammation tissues. Recent advances single-cell profiling techniques have transformed ability to examine fibroblast states populations inflamed tissues, providing evidence previously underappreciated heterogeneity disease-associated populations. These studies challenge preconceived notion that homogeneous provide new insights into role pathology. addition, molecular mechanisms activation reveal powerful cell-intrinsic amplification loops synergize with primary stimuli result striking responses. this Review, we focus recent developments our understanding pathology across tissues diseases. We highlight approaches to, applications of, what they teach us about biology. Finally, address how these could lead development novel therapeutic targeting disease.

Language: Английский

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Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade

Gut, Journal Year: 2023, Volume and Issue: 72(9), P. 1774 - 1782

Published: Jan. 27, 2023

Investigating the effect of ferroptosis in tumour microenvironment to identify combinatory therapy for liver cancer treatment.Glutathione peroxidase 4 (GPx4), which is considered master regulator ferroptosis, was genetically altered murine models hepatocellular carcinoma (HCC) and colorectal (CRC) analyse on cells immune microenvironment. The findings served as foundation identification additional targets combine with ferroptotic inducer treatment HCC metastasis.Surprisingly, hepatocyte-restricted GPx4 loss does not suppress tumourigenesis. Instead, GPx4-associated hepatocyte death causes a suppressive response characterised by CXCL10-dependent infiltration cytotoxic CD8+ T that counterbalanced PD-L1 upregulation well marked HMGB1-mediated myeloid derived suppressor cell (MDSC) infiltration. Blocking PD-1 or HMGB1 unleashes activation prolongs survival mice Gpx4-deficient tumours. A triple combination inducing natural compound withaferin A, CXCR2 inhibitor SB225002 α-PD-1 greatly improves wild-type In contrast, same affect growth subcutaneously grown CRC organoids, while it decreases their metastatic liver.Our data highlight context-specific ferroptosis-induced could be therapeutically exploited primary tumours metastases.

Language: Английский

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Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 27, 2024

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The receptor ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical signaling transduction. Accumulating evidence indicates that the pathway serves as both an oncogenic factor a tumor suppressor various cancer types. Dysregulation of this promotes epithelial-mesenchymal transition angiogenesis malignancies, closely linked proliferation, invasion, metastasis. Furthermore, contributes maintaining stem-like properties cells, thereby enhancing invasiveness. regulatory metabolic reprogramming microenvironment suggests pivotal involvement balancing suppressive effects. Moreover, implicated conferring chemoresistance cells. Therefore, comprehensive understanding these biological processes crucial developing innovative therapeutic strategies targeting signaling. This review focuses on research progress cancers, providing in-depth insights into potential mechanisms regulation occurrence progression cancer. Additionally, summarizes pharmaceutical clinical trials therapy, aiming offer new human malignancies.

Language: Английский

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Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy

Immunity, Journal Year: 2022, Volume and Issue: 55(11), P. 2059 - 2073.e8

Published: Oct. 19, 2022

T memory stem cells (TSCM) display increased self-renewal and prolonged survival capabilities, thus preventing cell exhaustion promoting effective anti-tumor responses. TSCM can be expanded by Urolithin A (UA), which is produced the commensal gut microbiome from foods rich in ellagitannins known to improve mitochondrial health. Oral UA administration tumor-bearing mice conferred strong CD8+ immunity, whereas ex vivo pre-treated displayed improved function upon adoptive transfer. UA-induced formation depended on Pink1-mediated mitophagy triggering cytosolic release of phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, drove Wnt signaling compensatory biogenesis. Collectively, we unravel a critical pathway linking suggest that well-tolerated metabolic compound represents an attractive option immune therapy.

Language: Английский

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Colorectal Cancer Organoid–Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(10), P. 2192 - 2211

Published: July 25, 2023

In colorectal cancers, the tumor microenvironment plays a key role in prognosis and therapy efficacy. Patient-derived organoids (PDTO) show enormous potential for preclinical testing; however, cultured cells lose important characteristics, including consensus molecular subtypes (CMS). To better reflect cellular heterogeneity, we established cancer organoid-stroma biobank of matched PDTOs cancer-associated fibroblasts (CAF) from 30 patients. Context-specific phenotyping showed that xenotransplantation or coculture with CAFs improves transcriptomic fidelity instructs subtype-specific stromal gene expression. Furthermore, functional profiling exposed CMS4-specific therapeutic resistance to gefitinib SN-38 prognostic expression signatures. Chemogenomic library screening identified patient- therapy-dependent mechanisms MET as common target. Our results demonstrate phenotypes are encrypted epithelium plastic fashion strongly depends on context. Consequently, essential faithful representation responses ex vivo. Systematic characterization provides resource context dependency cancer. We subtype memory is independent specific driver mutations. data underscore importance cocultures improved testing identification mechanisms. This article featured Selected Articles Issue, p. 2109.

Language: Английский

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Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Cancer Cell, Journal Year: 2025, Volume and Issue: 43(2), P. 269 - 291.e19

Published: Feb. 1, 2025

Highlights•Drugs currently used against irAEs reduce anti-tumor immunity•ECP induces adiponectin production in inflamed organs while sparing tumor tissue•ECP high response rates patients with ICI-induced irAEsSummaryImmune-related adverse events (irAEs) cancer receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that immunity is preserved mice after extracorporeal photopheresis (ECP) but reduced glucocorticosteroids, TNFα blockade, α4β7-integrin inhibition. Local elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies the colon tumor-specific development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) 14 reveals low ECP-related toxicity. Overall rate for all 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission 100% CI: 63.06%–100%). Glucocorticosteroid dosages could be ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory activation CD4+IFN-γ+ cells colitis without evidence loss immunity. In conclusion, identify as an immunomodulatory molecule controls blocking immunity.Graphical abstract

Language: Английский

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Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 12, 2025

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by complex interplay genetic, environmental, immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, Notch signaling pathway is instrumental governing cell fate decisions, tissue renewal, homeostasis, immune development. As highly conserved mechanism, not only modulates tumor behavior but also shapes landscape within microenvironment (TME). Aberrant fosters evasion progression through its effects on balance functionality cells, including myeloid-derived suppressor cells (MDSCs) tumor-associated macrophages (TAMs). Elevated activation correlates with advanced clinicopathological features poorer clinical outcomes, highlighting relevance as both prognostic biomarker therapeutic target. Therapeutic approaches aimed at inhibiting pathway, such γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) combination other therapies, have demonstrated promising efficacy preclinical settings. This review examines impact immunity, elucidating regulatory mechanisms role promoting progression. Additionally, this discusses strategies targeting signaling, GSIs, mAbs, potential therapies designed to overcome resistance improve patient outcomes. By multifaceted TME, underscores target for innovative strategies.

Language: Английский

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A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer

Cancer Research, Journal Year: 2020, Volume and Issue: 80(24), P. 5569 - 5582

Published: Oct. 14, 2020

Tumor progression is recognized as a result of an evolving cross-talk between tumor cells and their surrounding nontransformed stroma. Although Wnt signaling has been intensively studied in colorectal cancer, it remains unclear whether activity the tumor-associated stroma contributes to malignancy. To specifically interfere with stromal signals, we generated Wnt-independent organoids that secrete antagonist Sfrp1. Subcutaneous transplantation into immunocompetent well immunodeficient mice resulted strong reduction growth. Histologic transcriptomic analyses revealed Sfrp1 induced epithelial-mesenchymal transition (EMT) phenotype without affecting tumor-intrinsic signaling, suggesting involvement nonimmune cells. Blockage canonical using Sfrp1, Dkk1, or fibroblast-specific genetic ablation β-catenin strongly decreased number cancer-associated myofibroblasts (myCAF). CAFs was linked distinct subtypes, where low high levels inflammatory-like CAF (iCAF) subtype contractile myCAFs, respectively. Coculture iCAFs significant upregulation EMT markers, while myCAFs reverted this phenotype. In summary, show growth malignancy are differentially regulated via fibroblast subtypes under influence juxtacrine signals. SIGNIFICANCE: This study provides evidence for Wnt-induced functional diversity fibroblasts, representing non-cell autonomous mechanism colon cancer progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5569/F1.large.jpg.

Language: Английский

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