- by Rudawska, A., Szczygiel, A., Wegierek-Ciura, K., Mierzejewska, J., Kozien, D., Zeliszewska, P., Chaszczewska-Markowska, M., Rusiniak, P., Wator, K., Pedzich, Z., Pajtasz-Piasecka, E., Szermer-Olearnik, B.Background: Boron neutron capture therapy (BNCT) is a type of targeted radiotherapy that destroys boron-containing cancer cells using a neutron beam. It is intended for the treatment of patients with tumors that are resistant to conventional treatment, inoperable and recurrent. Therefore, it represents a promising therapy for the treatment of glioblastoma multiforme, the most aggressive stage IV cancer. To ensure high efficacy of BNCT, it is necessary to use selective boron carriers that deliver therapeutic doses of the boron-10 isotope […]
- by Thorseth, M.-L., Johansen, A. Z., Baker, K. J., Carretta, M., Roemer, A. M. A., Jensen, C., Jurgensen, H. J., Linder, H., Czajkowski, N. K., Kuczek, D. E., Fjaestad, K. Y., Engelholm, L. H., Willumsen, N., Kim, K., Andersen, M. H., Groentved, L., Madsen, D. H.Solid tumors are often characterized by a dense extracellular matrix (ECM) that contributes to increased tissue stiffness. Collagen type I is the main component of the ECM and its abundance in tumors is frequently associated with poor prognosis. In vitro studies suggest that a high collagen density promotes tumor invasion and modulates immune responses. However, recent in vivo findings have questioned the pro-tumorigenic role of collagen type I. In this study, we investigate the role of collagen for pancreatic tumor […]
- by Tschan, M., Jetzer, T., Obenloch, M., Blank, A., Yong, C., Nair, N., Cabon, L., DArcangelo, E., Lutolf, M.T cell bispecifics (TCBs) are potent immunotherapies with proven efficacy in hematological cancers but limited success in solid tumors, where on-target, off-tumor toxicity has restricted their therapeutic index. Clinical discontinuation of TCB formulations against epithelial cell adhesion molecule (EpCAM TCB, Solitomab) and preclinical termination of a TCB against folate receptor alpha (FolR1-TCB) highlight the urgent need for predictive preclinical models to evaluate such toxicities. Conventional models, including cell lines and organoids, lack the immune and stromal complexity of the tumor […]
- by Tyckaert, F., Göddertz, P. F., Reichhold, M., Sarg, B., Faserl, K., Paton Gonzalez, P., Eichin, F., Villunger, A., Ormanns, S., Redl, S., Hofmann, J., Hautz, T., Baschieri, F.Metastasis is the leading cause of cancer-related mortality, yet experimental models inadequately recapitulate the tissue-specific microenvironments that shape metastatic dissemination. In vivo systems provide physiological relevance but are poorly suited for mechanistic studies and screening, whereas conventional in vitro assays lack the organ-specific extracellular matrix (ECM) context that critically influences invasive behavior. To address this gap, an ex vivo method is established that balances biological relevance with scalability, affordability, and ease of use. Mild detergent decellularization of mouse organs followed […]
- by Rodriguez, M. A., Sivakumar, H., Popova, L., Derakhshesh, S., Chopyk, D., Miles, W. O., Dedhia, P. H., Skardal, A.Adrenocortical carcinoma (ACC) is an under-studied, aggressive cancer of the adrenal glands where surgical resection is currently the only effective curative option. However, after surgery the majority of patients experience tumor progression. The median overall survival of 12 months has not improved since approval of mitotane in 1970. The lack of effective therapies in ACC is partially due to the lack of preclinical models that accurately represent human ACC. Most attempts to generate ACC cell lines or animal models have […]
- by Kakkat, S., Suman, P., Goswami, S., Kola, B., Bruno, K., Frankel, W., Basu, S., Turbat-Herrera, E. A., Ramirez-Alcantara, V., Heslin, M., Andrews, J., Pramanik, P., Sarkar, C., Chakroborty, D.Background and Aims: Cell-cell attachment governed by tight junctions (TJs) is crucial for epithelial integrity, and the loss correlates with adverse outcomes in gastric cancer (GC). Restoration of TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies potential drivers of TJ disruption in GC to enable targeted intervention. Design: GC patient tissues, human GC cell lines, and orthotopic GC xenograft models were employed to investigate the role of the stomach renin angiotensin system (stRAS) in […]
- by Le Grand, M., Buxbaum, C., Kerherve, M., Gaucher, F., Martinez-Rubio, A., Taha, M., Muller, K., Mouysset, B., Bomane, A., Letard, S., Failes, T. W., Arndt, G. M., Chebbi, S., Labaronne, E., Cavalli, F. M. G., ANDRE, N., Broutier, L., Shaked, Y., Pasquier, E.Owing to chemoresistance, the prognosis of relapsed neuroblastoma is dismal with less than 10% of patients surviving after 5 years. We developed a reverse molecular pharmacology approach that is based on high-throughput drug screening coupled with chemo-informatic and transcriptomic analyses. This led to the identification of IRAK1 as a key chemoresistance factor in neuroblastoma. By performing functional and pharmacological drug combination screens targeting IRAK1, we revealed a synergy between IRAK1 inhibition/silencing and BET, EGFR and mTOR inhibitors as well as […]
- by Mastel, M., Guiseris Martinez, A., Diamante, G., Meier, J., Schuchmann, L., Georgakopoulos, N., Chiotakakos, I., Steffens, L. K., Artmann, C., Benitez, D., Guenther, M., Thiel, V., Pincheira, R., Trumpp, A., Offringa, R., Ormanns, S., Jackstadt, R.Immune evasion is a defining feature of advanced colorectal cancer (CRC), yet the cellular mechanisms linking cancer cell states to immune suppression remain poorly understood. To systematically map tumour-immune interactions in advanced CRC, we modelled recurrent human CRC mutations using a multiplex CRISPR-based genetically engineered mouse model platform. The resulting 20 models recapitulate key stages, genetic routes and histopathological features of human CRC, while single-cell transcriptomics reveals extensive disease complexity across models. Profiling of the epithelial tumour compartment identified a […]
- by Jacobson, D. H., McClurg, D. P., Black, E., Cassie, C., Cheung, T. S., Coles, H., Devonshire, G., Jammula, S., Hall, B., Li, X., Miremadi, A., Mahbubani, K. T., di Pietro, M., Saeb-Parsy, K., Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium,, Fitzgerald, R. C., Jones, C. M., Zhuang, L.Oesophageal adenocarcinoma (OAC) is a major cause of morbidity and mortality. OAC and its precursor, Barrett oesophagus (BO), are defined by substantial early heterogeneity, complicating prevention and treatment of OAC and remaining poorly recapitulated by current in vitro and animal model systems. We have generated 116 patient- and healthy donor- derived organoids (PDOs) spanning normal oesophagogastric tissue, BO and OAC. These PDOs capture population diversity and recapitulate phenotypic, genomic and transcriptomic features of their respective disease stages. We develop a […]
- by Sarre, C., Jerabkova-Roda, K., Denis, V., Bertolin, G., Tramier, M., Bochler, L., Liboni, C., Busnelli, I., Frenger, Q., Larnicol, A., Gros, F., Lefebvre, O., Guglielmi, L., Goetz, J. G., Hyenne, V., Martineau, P.This study successfully developed and validated isoform-specific intrabodies targeting the highly homologous Ral oncoproteins, key effectors in cancer progression. Phage display was used to isolate single-chain variable fragment (scFv) clones that recognize specifically RalA (C1-A, G5-A), RalB (F6-B), or both paralogs (A12-AB). Using lentiviral transduction, these intrabodies were stably expressed as GFP fusions in murine breast cancer 4T1 cells. The anti-RalA clones C1-A and A12-AB demonstrated clear colocalization with RalA, confirming their binding activity inside the cell. We further confirmed […]
- by Zhou, C., Crusher, J. T., Friesen, K., Twigger, S. A., Booker, G., Samuel, P., Parkes, E. E., Hammond, E. M.Hypoxia is a defining feature of triple-negative breast cancer (TNBC), driving invasion, metastasis, and therapy resistance. Understanding the molecular effectors of hypoxia is essential to identify new therapeutic targets. Here, we investigated tropomyosin 3 (TPM3), an actin-binding protein that regulates filament stability. TPM3 is significantly upregulated in breast cancer, including in TNBC, where elevated levels correlate with poor overall survival. Using validated hypoxia signatures and TNBC cell models, we show that TPM3 is induced in physiologically relevant hypoxic conditions in […]
- by Xu, H., Lee, S., Leser, F., Fedorova, O., Lu, P., Song, E., Touat, M., Eichmann, A., Iwasaki, A., Pyle, A. M., Thomas, J.-L.Glioblastoma (GBM), the most frequent and aggressive primary brain tumor, remains refractory to all current therapies including surgical resection, chemotherapy, radiotherapy and immunotherapy. Immunosuppressive mechanisms in the GBM tumor microenvironment contribute to the lack of anti-tumor adaptive immunity. We found that a subset of tumor associated macrophages (TAMs) can be repolarized into an anti-tumor phenotype via agonist stimulation of the retinoic acid-inducible gene I (RIGI), a cytosolic double-stranded RNA pattern recognition receptor (PRR). In silico analysis of adult GBM datasets […]
- by Kotagiri, V., Baker, E. A.Glioblastoma (GBM) remains the most lethal primary brain tumor, with median survival of 14-16 months despite aggressive multimodal therapy[1,2]. The failure of PD-1/PD-L1 checkpoint inhibitors in GBM (CheckMate-143)[3] has highlighted the need for alternative immunotherapeutic targets and companion diagnostics. CD276 (B7-H3) has emerged as a promising target, with multiple anti-B7-H3 therapies in clinical development including monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cells[4-6]. However, no validated companion diagnostic exists to stratify patients for these therapies. Here we present comprehensive validation […]
- by Klinke, D. J., Razazan, A., Pirkey, A. C., Deng, W.Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that is upregulated in essentially all invasive breast cancers and promotes immunosuppression in melanoma. Recent work suggests that limited anti-tumor immunity also associates with poor patient outcomes in patients with breast cancer. Motivated by increased CCN4 correlating with dampened anti-tumor immunity in primary breast cancer, we test for a direct causal link by knocking out CCN4 (CCN4 KO) in the Py230 and Py8119 mouse breast cancer […]
- by Chauvin, M., Roche-Prellezo, J., Lafont, V., Michaud, H.-A., Tromelin, E., Michel, R., Freixinos, C., Meinsohn, M.-C., Colombo, P.-E., Bonnefoy, N., Gros, L., Pepin, D.Cancer-associated mesothelial cells (CAMCs) are key modulators of the ovarian tumor microenvironment, contributing to tumor growth an immune evasion. Normal mesothelial cells play a role in peritoneal homeostasis and immune surveillance and represent the first point of contact during abdominal dissemination of ovarian cancers. Yet, their role in ovarian tumor immunity remains poorly understood. Here, we map the cellular states, spatial organization, and immune functions of CAMCs across ovarian cancer progression. Using lineage tracing and spatial transcriptomics, we demonstrate that […]
- by Ariyan, L. A., Zambalde, E., Li, J., McAuliffe, T. T., Ma, E., Martinez, F. P., Panarelli, N. C., Eddy, R. J., Patil, P., Condeelis, J., Gil-Henn, H., McAuliffe, J. C.Metastatic pancreatic ductal adenocarcinoma (PDAC) remains incurable and is projected to become the second leading cause of cancer-related death by 2030. Despite therapeutic advances, median survival remains under one year. Activating KRAS mutations drive the majority of PDAC and underlie their highly aggressive behavior. Although emerging KRAS inhibitors show promise, resistance limits their clinical efficacy, underscoring the need to identify additional regulators of mutant KRAS signaling. We investigated the role of the actin-regulatory protein Mena (ENAH) in KRASG12D-driven PDAC using […]
- by Lavoie, V., Jeong, W., Jeon, J., Andrade, J., Ali, A., Jurisica, I., Esfandiari, N., Leong, I., Yeo, H., Molska, G., Bradley, G., Bubola, J., Chugh, D., Magalhaes, M.Oral squamous cell carcinoma (OSCC) often arises from oral epithelial dysplasia (OED); however, the gene expression changes during OED progression and its microenvironment are not fully understood. This study used spatial transcriptomics to identify differentially expressed genes and microenvironmental alterations associated with OEDs malignant transformation of OED. A ten-year retrospective analysis of paired OSCC and prior OED samples was conducted at the University of Toronto Oral Pathology Laboratory. A total of 24 paired progressing OED cases and 23 matched non-progressing […]
- by Fardin, A., Benvenuto, A. F., Schiano Lomoriello, I., Tordonato, C., Quarto, M., Freddi, S., Giangreco, G., Bertalot, G., Montani, F., Colaluca, I. N., Cacciatore, R., Raimondi, A., Jodice, M. G., Malabarba, M. G., Scietti, L., Ciossani, G., Cuomo, A., Shafaq-Zadah, M., Dransart, E., Kanannejad, S., Green, B., Pece, S., Confalonieri, S., Nilsson, U. J., Leffler, H., Scita, G., Johannes, L., Di Fiore, P. P., Sigismund, S.Aberrant endocytosis has long been associated with epithelial plasticity and tumorigenesis, but direct in vivo evidence of its causal role in tumor progression and metastasis has been lacking. Here, we identify and molecularly characterize a previously unrecognized form of E-cadherin (ECAD) internalization in mammary epithelial cells. This process is mediated by the endocytic adaptor Epsin 3 (EPN3) through glycolipid-lectin (GL-Lect) driven endocytosis requiring galectin-3 and Eps15-family adaptors. Leveraging an EPN3 knock-in mouse model, we show that dysregulation of GL-Lect driven […]
- by Yu, X., Li, W., Feng, H., Li, Z., Zheng, H., Sun, S., Li, J., Li, B., Wu, Q.Diet profoundly shapes the tumor microenvironment through metabolite modulation, yet the mechanisms linking diet, gut microbiota, and antitumor immunity remain unclear. Here, we demonstrate that a mediterranean-mimicking diet (MedDiet) suppresses tumor growth by orchestrating a microbiota-metabolite-immune axis. MedDiet selectively enriched Bacteroides thetaiotaomicron (B. thetaiotaomicron) in the gut, whose administration recapitulated tumor suppression. Both MedDiet and B. thetaiotaomicron elevated plasma levels of the tryptophan metabolite indole-3-acetic acid (3-IAA). Mechanistically, 3-IAA enhanced CD8+ T cell cytotoxicity and alleviated exhaustion by inhibiting the […]
- by Mastel, M., Martinez, A. G., Pozza, U., Meier, J., Chiotakakos, I., Jaun, S., Diamante, G., Georgakopoulos, N., Albrecht, P., Petersen, Y., Reuter, S., Schmitt, B., Guenther, M., Nurfauziah, I., Ghezzi, I., Ouyang, K. S., Milsom, M., Puschhof, J., Reitsam, N. G., Boonekamp, K. E., Betge, J., Ormanns, S., Boutros, M., Jackstadt, R.BRAF-mutant colorectal cancer (CRC) constitutes a molecularly and clinically distinct subtype with poor prognosis and resistance to standard therapies, representing a major unmet clinical need. Arising from the serrated pathway of colorectal carcinogenesis rather than the classical adenoma-carcinoma sequence, this subgroup remains relatively understudied yet displays a more aggressive disease course. To investigate the progression of serrated CRC, we generated multiple genetically engineered mouse models (GEMMs) of BRAF-mutant, microsatellite-stable (MSS) CRC that closely recapitulate human disease. Our findings demonstrate that […]
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