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4. Tumor-targeting bacteria as immune stimulants – the future of cancer immunotherapy?

Author

Mowday, Alexandra M., van de Laak, Jella M., Fu, Zhe, Henare, Kimiora L., Dubois, Ludwig, Lambin, Philippe, Theys, Jan, and Patterson, Adam V.

Subjects
TYPE I interferons, TUMOR-infiltrating immune cells, TREATMENT effectiveness, TUMOR microenvironment, IMMUNE response
Abstract

Cancer immunotherapies have been widely hailed as a breakthrough for cancer treatment in the last decade, epitomized by the unprecedented results observed with checkpoint blockade. Even so, only a minority of patients currently achieve durable remissions. In general, responsive patients appear to have either a high number of tumor neoantigens, a preexisting immune cell infiltrate in the tumor microenvironment, or an 'immune-active' transcriptional profile, determined in part by the presence of a type I interferon gene signature. These observations suggest that the therapeutic efficacy of immunotherapy can be enhanced through strategies that release tumor neoantigens and/or produce a pro-inflammatory tumor microenvironment. In principle, exogenous tumor-targeting bacteria offer a unique solution for improving responsiveness to immunotherapy. This review discusses how tumor-selective bacterial infection can modulate the immunological microenvironment of the tumor and the potential for combination with cancer immunotherapy strategies to further increase therapeutic efficacy. In addition, we provide a perspective on the clinical translation of replicating bacterial therapies, with a focus on the challenges that must be resolved to ensure a successful outcome. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Targeted nutritional intervention attenuates experimental lung cancer cachexia

Author

Worp, Wouter R. P. H., Theys, Jan, Wolfs, Cecile J. A., Verhaegen, Frank, Schols, Annemie M. W. J., Helvoort, Ardy, and Langen, Ramon C. J.

Abstract

Cachexia, a syndrome with high prevalence in non‐small cell lung cancer patients, impairs quality of life and reduces tolerance and responsiveness to cancer therapy resulting in decreased survival. Optimal nutritional care is pivotal in the treatment of cachexia and a recommended cornerstone of multimodal therapy. Here, we investigated the therapeutic effect of an intervention diet consisting of a specific combination of high protein, leucine, fish oil, vitamin D, galacto‐oligosaccharides, and fructo‐oligosaccharides on the development and progression of cachexia in an orthotopic lung cancer mouse model. Eleven‐week‐old male 129S2/Sv mice were orthotopically implanted with 344P lung epithelial tumour cells or vehicle (control). Seven days post‐implantation tumour‐bearing (TB) mice were allocated to either intervention‐ or isocaloric control diet. Cachexia was defined as 5 days of consecutive body weight loss, after which mice were euthanized for tissue analyses. TB mice developed cachexia accompanied by significant loss of skeletal muscle mass and epididymal fat mass compared with sham operated mice. The cachectic endpoint was significantly delayed (46.0 ± 15.2 vs. 34.7 ± 11.4 days), and the amount (−1.57 ± 0.62 vs. −2.13 ± 0.57 g) and progression (−0.26 ± 0.14 vs. −0.39 ± 0.11 g/day) of body weight loss were significantly reduced by the intervention compared with control diet. Moreover, systemic inflammation (pentraxin‐2 plasma levels) and alterations in molecular markers for proteolysis and protein synthesis, indicative of muscle atrophy signalling in TB‐mice, were suppressed in skeletal muscle by the intervention diet. Together, these data demonstrate the potential of this multinutrient intervention, targeting multiple components of cachexia, as integral part of lung cancer management.

Published
2024
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14. A novel orthotopic mouse model replicates human lung cancer cachexia

Author

van de Worp, Wouter R.P.H., primary, Theys, Jan, additional, González, Alba Sanz, additional, van der Heyden, Brent, additional, Verhaegen, Frank, additional, Hauser, Duncan, additional, Caiment, Florian, additional, Smeets, Hubertus J.M., additional, Schols, Annemie M.W.J., additional, van Helvoort, Ardy, additional, and Langen, Ramon C.J., additional

Published
2023
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15. Data from Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Author

Narayan, Ravi S., primary, Gasol, Ana, primary, Slangen, Paul L.G., primary, Cornelissen, Fleur M.G., primary, Lagerweij, Tonny, primary, Veldman, Hou Y.Y.E., primary, Dik, Rogier, primary, van den Berg, Jaap, primary, Slotman, Ben J., primary, Würdinger, Tom, primary, Haas-Kogan, Daphne A., primary, Stalpers, Lukas J.A., primary, Baumert, Brigitta G., primary, Westerman, Bart A., primary, Theys, Jan, primary, and Sminia, Peter, primary

Published
2023
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16. Supplemental Figures 1-7 and Tables 1-2 from Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Author

Narayan, Ravi S., primary, Gasol, Ana, primary, Slangen, Paul L.G., primary, Cornelissen, Fleur M.G., primary, Lagerweij, Tonny, primary, Veldman, Hou Y.Y.E., primary, Dik, Rogier, primary, van den Berg, Jaap, primary, Slotman, Ben J., primary, Würdinger, Tom, primary, Haas-Kogan, Daphne A., primary, Stalpers, Lukas J.A., primary, Baumert, Brigitta G., primary, Westerman, Bart A., primary, Theys, Jan, primary, and Sminia, Peter, primary

Published
2023
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17. Supplementary Methods and Material from A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure–Cancer Associations

Author

Ertaylan, Gökhan, primary, Le Cornet, Charlotte, primary, van Roekel, Eline H., primary, Jung, Audrey Y., primary, Bours, Martijn J.L., primary, Damms-Machado, Antje, primary, van den Brandt, Piet A., primary, Schock, Helena, primary, de Kok, Theo M., primary, Theys, Jan, primary, Arts, Ilja C.W., primary, Kaaks, Rudolf, primary, Weijenberg, Matty P., primary, and Fortner, Renée Turzanski, primary

Published
2023
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18. Data from A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure–Cancer Associations

Author

Ertaylan, Gökhan, primary, Le Cornet, Charlotte, primary, van Roekel, Eline H., primary, Jung, Audrey Y., primary, Bours, Martijn J.L., primary, Damms-Machado, Antje, primary, van den Brandt, Piet A., primary, Schock, Helena, primary, de Kok, Theo M., primary, Theys, Jan, primary, Arts, Ilja C.W., primary, Kaaks, Rudolf, primary, Weijenberg, Matty P., primary, and Fortner, Renée Turzanski, primary

Published
2023
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19. The Modulatory Effects of Fatty Acids on Cancer Progression

Author

Westheim, Annemarie J. F., primary, Stoffels, Lara M., additional, Dubois, Ludwig J., additional, van Bergenhenegouwen, Jeroen, additional, van Helvoort, Ardy, additional, Langen, Ramon C. J., additional, Shiri-Sverdlov, Ronit, additional, and Theys, Jan, additional

Published
2023
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32. Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506

Author

van der Wiel, Alexander M.A., primary, Jackson-Patel, Victoria, additional, Niemans, Raymon, additional, Yaromina, Ala, additional, Liu, Emily, additional, Marcus, Damiënne, additional, Mowday, Alexandra M., additional, Lieuwes, Natasja G., additional, Biemans, Rianne, additional, Lin, Xiaojing, additional, Fu, Zhe, additional, Kumara, Sisira, additional, Jochems, Arthur, additional, Ashoorzadeh, Amir, additional, Anderson, Robert F., additional, Hicks, Kevin O., additional, Bull, Matthew R., additional, Abbattista, Maria R., additional, Guise, Christopher P., additional, Deschoemaeker, Sofie, additional, Thiolloy, Sophie, additional, Heyerick, Arne, additional, Solivio, Morwena J., additional, Balbo, Silvia, additional, Smaill, Jeff B., additional, Theys, Jan, additional, Dubois, Ludwig J., additional, Patterson, Adam V., additional, and Lambin, Philippe, additional

Published
2021
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33. A novel orthotopic mouse model replicates human lung cancer cachexia

Author

Worp, Wouter R.P.H., Theys, Jan, González, Alba Sanz, Heyden, Brent, Verhaegen, Frank, Hauser, Duncan, Caiment, Florian, Smeets, Hubertus J.M., Schols, Annemie M.W.J., Helvoort, Ardy, and Langen, Ramon C.J.

Abstract

Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour‐bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle‐specific alterations associated with human lung cancer cachexia. Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour‐bearing group. Syngeneic lung epithelium‐derived adenocarcinoma cells (K‐rasG12D; p53R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis. Two‐third of the tumour‐bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; P< 0.01), muscle mass (−13.8 ± 8.1%; P< 0.01) and muscle strength (−25.5 ± 10.5%; P< 0.001) were reduced in cachectic mice compared with sham controls and median survival time post‐surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32and Trim63) and autophagy‐lysosomal pathway (Gabarapl1and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E‐BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin‐2 (P< 0.001) and CXCL1/KC (P< 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P< 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia. We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.

Published
2023
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39. Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice

Author

Yadati, Tulasi, primary, Houben, Tom, additional, Bitorina, Albert, additional, Oligschlaeger, Yvonne, additional, Gijbels, Marion J., additional, Mohren, Ronny, additional, Lütjohann, Dieter, additional, Khurana, Princy, additional, Goyal, Sandeep, additional, Kulkarni, Aditya, additional, Theys, Jan, additional, Cillero-Pastor, Berta, additional, and Shiri-Sverdlov, Ronit, additional

Published
2021
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42. Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506

Author

Wiel, Alexander M.A. van der, primary, Jackson-Patel, Victoria, additional, Niemans, Raymon, additional, Yaromina, Ala, additional, Liu, Emily, additional, Marcus, Damiënne, additional, Mowday, Alexandra, additional, Lieuwes, Natasja, additional, Biemans, Rianne, additional, Lin, Xiaojing, additional, Fu, Zhe, additional, Kumara, Sisira, additional, Jochems, Arthur, additional, Ashoorzadeh, Amir, additional, Anderson, Robert, additional, Hicks, Kevin, additional, Bull, Matthew, additional, Abbattista, Maria, additional, Guise, Christopher, additional, Deschoemaeker, Sofie, additional, Thiolloy, Sophie, additional, Heyerick, Arne, additional, Solivio, Morwena, additional, Balbo, Silvia, additional, Smaill, Jeff, additional, Theys, Jan, additional, Dubois, Ludwig, additional, Patterson, Adam, additional, and Lambin, Philippe, additional

Published
2021
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43. Automated CT-derived skeletal muscle mass determination in lower hind limbs of mice using a 3D U-Net deep learning network

Author

van der Heyden, Brent, van der Heyden, Brent, van de Worp, Wouter R. P. H., van Helvoort, Ardy, Theys, Jan, Schols, Annemie M. W. J., Langen, Ramon C. J., Verhaegen, Frank, van der Heyden, Brent, van der Heyden, Brent, van de Worp, Wouter R. P. H., van Helvoort, Ardy, Theys, Jan, Schols, Annemie M. W. J., Langen, Ramon C. J., and Verhaegen, Frank

Abstract

The loss of skeletal muscle mass is recognized as a complication of several chronic diseases and is associated with increased mortality and a decreased quality of life. Relevant and reliable animal models in which muscle wasting can be monitored noninvasively over time are instrumental to investigate and develop new therapies. In this work, we developed a fully automatic deep learning algorithm for segmentation of micro cone beam computed tomography images of the lower limb muscle complex in mice and subsequent muscle mass calculation. A deep learning algorithm was trained on manually segmented data from 32 mice. Muscle wet mass measurements were obtained from 47 mice and served as a data set for model validation and reverse model validation. The automatic algorithm performance was similar to 150 times faster than manual segmentation. Reverse validation of the algorithm showed high quantitative metrics (i.e., a Dice similarity coefficient of 0.93. a Hausdorff distance of 0.4 mm, and a center of mass displacement of 0.1 mm). substantiating the robustness and accuracy of the model. A high correlation (R-2 = 0.92) was obtained between the computed tomography-derived muscle mass measurements and the muscle wet masses. Longitudinal follow-up revealed time-dependent changes in muscle mass that separated control from lung tumor-bearing mice, which was confirmed as cachexia. In conclusion, this deep learning model for automated assessment of the lower limb muscle complex provides highly accurate noninvasive longitudinal evaluation of skeletal muscle mass. Furthermore, it facilitates the workflow and increases the amount of data derived from mouse studies while reducing the animal numbers.NEW & NOTEWORTHY This deep learning application enables highly accurate noninvasive longitudinal evaluation of skeletal muscle mass changes in mice with minimal requirement for operator involvement in the data analysis. It provides a unique opportunity to increase and analyze

Published
2020

44. Identification of microRNAs in skeletal muscle associated with lung cancer cachexia

Author

van de Worp, Wouter R.P.H., Schols, Annemie M.W.J., Dingemans, Anne Marie C., Op den Kamp, Céline M.H., Degens, Juliette H.R.J., Kelders, Marco C.J.M., Coort, Susan, Woodruff, Henry C., Kratassiouk, Gueorqui, Harel-Bellan, Annick, Theys, Jan, van Helvoort, Ardy, Langen, Ramon C.J., van de Worp, Wouter R.P.H., Schols, Annemie M.W.J., Dingemans, Anne Marie C., Op den Kamp, Céline M.H., Degens, Juliette H.R.J., Kelders, Marco C.J.M., Coort, Susan, Woodruff, Henry C., Kratassiouk, Gueorqui, Harel-Bellan, Annick, Theys, Jan, van Helvoort, Ardy, and Langen, Ramon C.J.

Abstract

Background: Cachexia, highly prevalent in patients with non-small cell lung cancer (NSCLC), impairs quality of life and is associated with reduced tolerance and responsiveness to cancer therapy and decreased survival. MicroRNAs (miRNAs) are small non-coding RNAs that play a central role in post-transcriptional gene regulation. Changes in intramuscular levels of miRNAs have been implicated in muscle wasting conditions. Here, we aimed to identify miRNAs that are differentially expressed in skeletal muscle of cachectic lung cancer patients to increase our understanding of cachexia and to allow us to probe their potential as therapeutic targets. Methods: A total of 754 unique miRNAs were profiled and analysed in vastus lateralis muscle biopsies of newly diagnosed treatment-naïve NSCLC patients with cachexia (n = 8) and age-matched and sex-matched healthy controls (n = 8). miRNA expression analysis was performed using a TaqMan MicroRNA Array. In silico network analysis was performed on all significant differentially expressed miRNAs. Differential expression of the top-ranked miRNAs was confirmed using reverse transcription–quantitative real-time PCR in an extended group (n = 48) consisting of NSCLC patients with (n = 15) and without cachexia (n = 11) and healthy controls (n = 22). Finally, these miRNAs were subjected to univariate and multivariate Cox proportional hazard analysis using overall survival and treatment-induced toxicity data obtained during the follow-up of this group of patients. Results: We identified 28 significant differentially expressed miRNAs, of which five miRNAs were up-regulated and 23 were down-regulated. In silico miRNA-target prediction analysis showed 158 functional gene targets, and pathway analysis identified 22 pathways related to the degenerative or regenerative processes of muscle tissue. Subsequently, the expression of six top-ranked miRNAs was measured in muscle biopsies of the entire patient group. Five miRNAs were detectable with re

Published
2020

48. Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19–IL2 cures poorly immunogenic tumors when combined with radiotherapy

Author

Olivo Pimentel, Veronica, primary, Marcus, Damiënne, additional, van der Wiel, Alexander MA, additional, Lieuwes, Natasja G, additional, Biemans, Rianne, additional, Lieverse, Relinde IY, additional, Neri, Dario, additional, Theys, Jan, additional, Yaromina, Ala, additional, Dubois, Ludwig J, additional, and Lambin, Philippe, additional

Published
2021
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49. Use of an optimised enzyme/prodrug combination for Clostridia directed enzyme prodrug therapy induces a significant growth delay in necrotic tumours

Author

Mowday, Alexandra M., primary, Dubois, Ludwig J., additional, Kubiak, Aleksandra M., additional, Chan-Hyams, Jasmine V. E., additional, Guise, Christopher P., additional, Ashoorzadeh, Amir, additional, Lambin, Philippe, additional, Ackerley, David F., additional, Smaill, Jeff B., additional, Minton, Nigel P., additional, Theys, Jan, additional, and Patterson, Adam V., additional

Published
2021
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50. OxLDL as an Inducer of a Metabolic Shift in Cancer Cells

Author

Bitorina, Albert V., primary, Oligschlaeger, Yvonne, additional, Ding, Lingling, additional, Yadati, Tulasi, additional, Westheim, Annemarie, additional, Houben, Tom, additional, Vaes, Rianne D.W., additional, Olde Damink, Steven W.M., additional, Theys, Jan, additional, and Shiri-Sverdlov, Ronit, additional

Published
2021
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