- by Bose, M., Ruoff, C. J., Ehsan, S. F., Stewart, C. A., Duarte, A., Bhattacharyya, S., Li, J., Anchang, B., Welte, T., Victorian, A., Lujan, F. E., Diao, L., Wang, J., Chen, K., Zhang, B., Wang, R., Solis Soto, L. M., Serrano, A. G., Cardnell, R., Gay, C. M., Byers, L., Karacosta, L. G.Small-cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by high numbers of circulating tumor cells (CTCs). We applied CyTOF and a 20-marker antibody panel to detect and phenotype CTCs directly in liquid biopsies of 51 SCLC patients (treatment-naive, chemotherapy and immunotherapy-treated, and tarlatamab-treated), of which a subset were longitudinally tracked. Unsupervised clustering revealed distinct cell populations enriched in patient liquid biopsies compared to those from healthy donors. Further analysis identified CTC populations of the three established SCLC subtypes […]
- by Monteiro, J. S., Alecrim, L. C., Giordano, R. J., Setubal, J. C.Cancer and many ophthalmic diseases share angiogenesis as a common element for disease progression. Using a well-accepted animal model, we performed network coexpression analysis of mRNA and regulatory RNA to investigate the molecular landscape of pathological angiogenesis in the mouse retina. We assessed the relevance of the RNA coexpression analysis by building gene signatures for breast cancer (METABRIC cohort). Most of the gene signatures were prognostic, and one was prognostic for HER2+ breast cancer, outperforming previously reported HER2+ signatures. Interestingly, […]
- by Paul, A., Joshi, G., Jungk, P., Kaur, S., Yao, S., Tsirkas, I., Boehly, N., Sitte, M., Salinas, G., Hamperl, S., Kschischo, M., Bastians, H.Cancer chromosomal instability (CIN) drives tumor evolution through generating structural and numerical chromosome aberrations. However, its molecular determinants remain poorly characterized. Here, we uncover a yet unrecognized role for the tumor suppressor SMAD4 as a key regulator of genome stability. Mechanistically, loss of SMAD4 induces replication stress by promoting transcription-replication conflicts (TRCs), which induces chromosomal breaks and subsequent mitotic errors, leading to the concomitant emergence of structural and numerical CIN. While the tumor suppressor function of SMAD4 has been predominantly […]
- by Pakulska, U., Obacz, M., Woznicki, J., Wiklik, K., Chakraborty, S., Micek, M., Mohanty, V., Coelho, D., Adamczyk, E., Golas, A., Moszynska, A., Zhang, H., Cybulska-Lubak, M., Kaniuga, E., Sadowska-Markiewicz, Z., Konopleva, M., Mikula, M., Juszczynski, P., Shastri, A., Baran, N., Rzymski, T., Mazan, M.The combination of venetoclax (VEN) and hypomethylating agents (HMA) is the standard of care in acute myeloid leukemia (AML) for elderly patients unfit for intensive chemotherapy. Despite its clinical success, most patients eventually relapse, creating an urgent need for effective therapeutic alternatives. In this study, we aimed to evaluate the potential of romaciclib, a first-in-class CDK8/CDK19 inhibitor, in combination with VEN to overcome stroma-mediated and primary/acquired VEN-resistance. We assessed the efficacy of RVU120+VEN combination in both sensitive and resistant AML […]
- by Bigot, J., Bouttier, M., Fregona, V., Rouzier, C., Bayet, M., Hebrard, S., Prade, N., Lagarde, S., Didier, C., Largeaud, L., Vergez, F., Quillet-Mary, A., Ysebaert, L., Broccardo, C., Baruchel, A., Strullu, M., Clappier, E., Pasquet, M., Lainey, E., Delabesse, E., Gerby, B.Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is effectively controlled with contemporary multi-agent chemotherapy, resulting to 5-year survival rates above 90%. However, relapse occurs in 15-20% of patients due to minimal residual disease (MRD), characterized by the presence of persisting and resistant leukemic cells, and associated with a poor clinical outcome. Despite its prognostic relevance, the molecular features driving MRD are poorly characterized. In this study, we developed patient-derived xenograft (PDX) models from matched diagnosis and relapse B-ALL samples combined to […]
- by Hernandez, M., Shin, S., Rengel, D., Dauvillier, S., Geoffre, N., Valle, C., Taccini, A., Moutahir, M., Bertrand-Michel, J., Reina, N., Muller, C., Attane, C.Bone is the main metastatic site in advanced prostate cancer (PCa) and contains bone marrow adipocytes (BMAds), which account for more than 70% of adult bone marrow. However, their role in the progression of PCa metastases remains poorly understood. Herein, we developed a physiologically relevant 3D culture model using primary human BMAds from red hematopoietic rich-areas (rBMAds) and we showed that rBMAds engage in metabolic crosstalk with PCa cells. Specifically, rBMAds release free fatty acids (FFAs) through a non-canonical lipolytic […]
- by Chang, C.-C., Shi, L., Choi, S. H., Pennati, A., Valkanioti, V., Capitini, C. M., Mecozzi, S., Galipeau, J.AbstractEngineering T and natural killer (NK) cells with chimeric antigen receptors (CAR) creates effective adoptive cell transfer therapies for cancer treatment. However, using viral transduction as a primary genetic modification method adds regulatory burdens and is expensive to produce at scale. Delivering mRNA encoding CAR via lipid nanoparticles (LNPs) has been explored as a potent non-viral method to generate CAR immune cells. Still, it has not been optimized for CAR treatment of neuroblastoma to date. An LNP formulation to deliver […]
- by Zhang, X., Barrios, A., Higgins, L., Markowski, T., Murray, K., Witthuhn, B., Yang, T.-Y., Yee, D.The insulin receptor (IR) is expressed in breast cancer cells and plays a role in regulating tumor biology. There are two IR isoforms generated from the same gene. Alternate splicing with exclusion or inclusion of exon 11accounts for the two isoforms. The exon 11 excluded isoform (IR-A) is expressed during fetal development while the full-length adult IR (IR-B) is the primary form expressed during adult life. This splice variant results in a 12 amino acid variation in peptide sequence. Breast […]
- by Fernandez-Barral, A., Barbachano, A., Rodriguez-Marrero, S., del Peso, L., Herreros-Cabello, A., Rodriguez-Salas, N., Prieto, I., Burgos, A., Leon-Arellano, M., Garcia-Olmo, D., Olleros, T., Gonzalez-Sancho, J. M., Larriba, M. J., Munoz, A.Early-onset colorectal cancer (EO-CRC,
- by Gajic, N., Christie, R., Lam, S., Ackermann, T., Himonas, E., Josephs-Spaulding, J., Manoharan, A., Assmann, V., Martin, J., Collings, A., Dunn, K., Shokry, E., Uribe, A. H., Burns, S., O'Connor, D., Mansour, M. R., Sumpton, D., Helgason, G. V., Voorde, J. V., Tardito, S., Tait, S. W., Halsey, C.The leptomeninges present a challenging tumour microenvironment with cells receiving low levels of nutrients and oxygen from cerebrospinal fluid (CSF), however these metabolic constraints are yet to be exploited therapeutically. Central nervous system (CNS) relapse in acute lymphoblastic leukaemia (ALL) remains a formidable clinical challenge because the leptomeningeal niche restricts drug penetration and immune surveillance. Current CNS-directed treatments rely on neurotoxic intrathecal chemotherapy, underscoring the urgent need for novel targeted strategies. Here, we uncover a profound niche-specific metabolic vulnerability in […]
- by Kitamura, T., Fujino, T., Ochi, Y., Goyama, S., Shimosato, Y., Shikata, S., Kon, A., Mori, T., Sakata, T., Honda, H., Koseki, H., Nakayama, M., Shirahige, K., Miyano, S., Ogawa, S.Gene expressions are regulated by an interplay between epigenetics and spatial genome organization, the deregulation of which has been implicated in the development of cancers, including myeloid neoplasms. However, it is unclear how they coordinately contribute to normal and malignant hematopoiesis. Here, we show that simultaneous dysregulations of histone modifications and chromatin structures caused by mutations of the epigenetic modulator Asxl1 and cohesin subunit Stag2 cooperatively induce ectopic interactions between polycomb-regulated promoters and active enhancers, leading to the aberrant upregulation […]
- by De Luca, V., Hansen, N., Digumarti, P., Tang, N., Fink, K., Snipes, G., Pirrotte, P., Berens, M.Radiation-induced senescence (RIS) in glioblastoma (GBM) is an undesirable cell fate that inhibits tumor cell death and supports resistance and outgrowth. While senescence-targeting drugs are promising adjuvants, their clinical application will require proper patient selection based on post-treatment RIS burden. Current methods to evaluate senescence, however, are tissue-based, and given GBMs difficult anatomical location, post-treatment biopsies are impractical. Therefore, novel and less invasive biomarkers for TIS are urgently needed. To this end, we aimed to identify candidate extracellular vesicle (EV) […]
- by Mustafa, A.-H. M., Pons, M., Mahendrarajah, N., Wiegerling, M., Hartkamp, J., Christmann, M., Radsak, M. P., Schneider, G., Wirth, M., Kramer, O. H.Histone deacetylases (HDACs) are key epigenetic regulators that are frequently dysregulated in cancer cells. Context-specific dependencies of tumor cell survival on HDACs and the mechanisms through which HDACs determine cell stress responses by specific oncogenic pathways remain to be understood. Here we unravel how the class I deacetylases HDAC1 and HDAC2 control the fate of chronic myeloid leukemia (CML) cells undergoing DNA replication stress. Compared to normal myeloid cells (n=690), CML cells overexpress HDAC1 and HDAC2 (n=234-274). We reveal that […]
- by Dymova, M., Koshmanova, A., Luzan, N., Morozov, E., Vasileva, N., Ageenko, A., Kahanova, V., Kolovskaya, O., Garkusha, T., Kichkailo, A., Kuligina, E., Richter, V.Virotherapy represents a promising approach for cancer treatment. However, when administered intravenously, oncolytic viruses are often hampered by neutralization from antibodies, reducing their antitumor efficacy. Aptamers offer a potential solution by shielding viral particles from neutralizing antibodies and prevent viral particle aggregation. In this study, human glioblastoma xenografts were orthotopically implanted in immunocompromised ICR mice. The therapeutic agents (VV-GMCSF-Lact-Apt1, VV-GMCSF-Lact-Apt2 or VV-GMCSF-Lact) were administered intravenously. Using magnetic resonance imaging, we observed a decrease in tumor growth in all experimental groups. […]
- by Li, Z., Zhang, Y., Tang, B., Xu, S., Zhu, Z., Wang, J., Ou, G., Hong, J., Qiu, M., Yang, H.Targeting DNA damage repair pathways represents a promising strategy in cancer radiotherapy, however, the limited insight into the regulation of the non-homologous end joining (NHEJ) repair pathway in cancer cells severely restricts the development of precise radiosensitization approaches. Here, we identify Reprimo (RPRM), a p53-inducible tumor suppressor, is a potent inhibitor of NHEJ in which RPRM promotes proteasomal degradation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylated at the T2609 site. Upon irradiation, RPRM quickly translocates into the nucleus to […]
- by O'Brien, E. T.Most deaths from cancer are caused by their metastases. Along with the ability to evade the immune system and to invade and disrupt very different tissue environments, metastases usually develop resistance to whatever therapeutic approaches are tried. Their extreme adaptability requires a diversity of traits from which natural selection can choose, but current models, such as the epithelial-to-mesenchymal transition (EMT), do not directly address how this diversity is generated. We observed that single cell clones of Panc1 human pancreas cancer […]
- by Escudeiro-Lopes, S., Gonzalez-Morena, J. M., Baudysova, A., Svoboda, M., Marasek, P., Rodriguez-Gomez, G., Ferreira Mendes, J., Phang, C. W., Miryala, S. K., Jakoube, P., Kovarova, B., Machado, S., Feng, Y., Keckesova, Z.Tumor suppressors represent one of the first lines of defense against malignant transformation and their inactivation in cells leads to onset of tumorigenesis. Cancer cells employ a variety of ways to inactivate cellular tumor suppressors, such as their epigenetic silencing or mutagenesis. Less understood are mechanisms by which cancer cells inactivate tumor suppressors post-translationally. Here, we uncovered a previously undescribed post-translational strategy that cancer cells use to inactivate the potent mitochondrial tumor suppressor LACTB in breast cancers. We discovered that […]
- by Choudhary, M., Chaudhary, M., Malik, N., Chosdol, K., Kushwaha, S., Sahu, A. K., Chowdhury, S., Bissa, B., Chowdhury, R., Mukherjee, S.BackgroundEpithelial to mesenchymal transition (EMT), a differentiation process, frequently imparts invasive properties in Glioblastoma Multiforme (GBM), which leads to a poor prognosis. Cells lose apical-basal polarity, cell-cell connections, and/or chemo-resistance during EMT, which can result in the spread of cancer and the acquisition of additional stem cell-like traits. It is unclear how organelle dynamics influence EMT in this respect. The interaction between cytoskeletal and mitochondrial regulators governing GBM cell EMT is explored in this article. Results and DiscussionIn GBM cells, […]
- by Seghers, S., Le Compte, M., Rodrigues Fortes, F., Baroen, J., Roeyen, G., Hartman, V., Kumar-Singh, S., Coppens, L., de Maat, M., Komen, N., Van den Broeck, S., Valk, J., Tjalma, W., Hendriks, j. M. H., Van Schil, P., Van Haesendonck, G., Peeters, S., Prenen, H., Deben, C.BackgroundPatient-derived tumor organoids (PDTOs) are strongly influenced by culture medium. We compared OncoPro (OP) Tumoroid Culture medium with conventional Wnt/R-spondin medium (Wnt). This recently developed OP medium offers a standardized, serum-free alternative to Wnt-based formulations. MethodsWe performed a comparison of OP and Wnt media across 36 PDTO lines from various malignancies. PDTOs were assessed for establishment success, morphology, transcriptomic profiles (bulk RNAseq and fidelity to public single cell (sc) RNAseq databases) and pharmacologic response to a 60-drug panel. ResultsAdaptation to […]
- by Bessler, N., Wezenaar, A. K. L., Ariese, H. C. R., Honhoff, C., Wehrens, E. J., Dommann, N., Ruiz Moreno, C., van den Broek, T., Collot, R. V. U., Kloosterman, D. J., Keramati, F., Roosen, M., de Blank, S., van Vliet, E., Barrera Roman, M., Gatti, L. C. D. E., Erturk, A., Kuball, J., Sebestyen, Z., Kool, M., Patrizi, S., Miele, E., Kunkele, A., Kranendonk, M. E. G., Cornel, A. M., Nierkens, S., Mayer, C., Stunnenberg, H. G., Alemany, A., Alieva, M., Rios, A. C.Diffuse midline glioma (DMG) is a rare yet highly aggressive paediatric cancer primarily arising in the pontine region of the brainstem, necessitating the development of scalable patient-representative models for treatment advance1,2. Here, we developed an FGF4-driven human brainstem organoid model, with high representation of pontine glial lineages. By genetically engineering de novo H3.3K27M-altered DMG, we show that this brainstem glial specification is essential for driving DMG tumorigenesis, resulting in tumours that recapitulate the infiltrative nature and molecular heterogeneity of patient […]
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