Search

Your search keyword '"Dijkstra, Krijn"' showing total 2 results
Start Over Author "Dijkstra, Krijn" Journal cancer discovery
2 results on '"Dijkstra, Krijn"'

1. Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Picco, Gabriele, Cattaneo, Chiara Maria, van Vliet, Esmee J, Crisafulli, Giovanni, Rospo, Giuseppe, Consonni, Sarah, Vieira, Sara Filipa, Sanchez Rodriguez, Inigo, Cancelliere, Carlotta, Banerjee, Ruby, Schipper, Luuk Johan, Oddo, Daniele, Dijkstra, Krijn Kristian, Cinatl, Jindrich, Michaelis, Martin, Yang, Fengtang, Uk Group, Cell Model Network, Di Nicolantonio, Federica, Sartore-Bianchi, Andrea, Siena, Salvatore, Arena, Sabrina, Voest, Emile E, Bardelli, Alberto, and Garnett, Mathew J

Subjects
Oncology, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Werner Syndrome Helicase, Colorectal cancer, medicine.medical_treatment, Synthetic lethality, Disease, DNA Mismatch Repair, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Drug Therapy, Internal medicine, Humans, Medicine, Molecular Targeted Therapy, 030304 developmental biology, Werner syndrome, 0303 health sciences, Chemotherapy, business.industry, nutritional and metabolic diseases, Immunotherapy, medicine.disease, 3. Good health, DNA mismatch repair, Colorectal Neoplasms, business, 030217 neurology & neurosurgery
Abstract

Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. Significance: We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy. This article is highlighted in the In This Issue feature, p. 1861

Published
2021

2. Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.

Author

Enfield KSS, Colliver E, Lee C, Magness A, Moore DA, Sivakumar M, Grigoriadis K, Pich O, Karasaki T, Hobson PS, Levi D, Veeriah S, Puttick C, Nye EL, Green M, Dijkstra KK, Shimato M, Akarca AU, Marafioti T, Salgado R, Hackshaw A, Jamal-Hanjani M, van Maldegem F, McGranahan N, Glass B, Pulaski H, Walk E, Reading JL, Quezada SA, Hiley CT, Downward J, Sahai E, Swanton C, and Angelova M

Subjects
Humans, T-Lymphocytes immunology, Myeloid Cells immunology, Female, Male, Immune Evasion, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms genetics, Tumor Microenvironment immunology
Abstract

Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis., Significance: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results