- by Saenz, F. R., Velasquez, B., Waldrop, T., Aguilar, E., Cox, K. R., Delahoussaye, A., Laberiano-Fernandez, C., Campos Clemente, L., Connell, L., Mims, N., Neill, D., Parra, E. R., Clise-Dwyer, K., Schueler, E., Spiotto, M. T.Radiotherapy (RT) delivered at conventional dose rates (CONV) can both stimulate antitumor immune responses and inhibit these immune responses by depleting circulating lymphocytes. Given the observed normal tissue sparing associated with ultra-high dose rate (FLASH) RT, we hypothesized that FLASH RT may protect lymphocytes while increasing the immunogenicity of cancer cells. We irradiated cancer cell lines in vitro with FLASH RT or CONV RT and assessed immunogenic mRNA and protein expression. Both HPV-positive cell lines MEER and TC-1 showed upregulation […]
- by Rokugo, M., Nakamura, K., Matsumoto, M., Endo, A., Nguyen, L. C., Nishizawa, H., Shima, R., Kashiwagi, H., Okoshi, A., Nakanome, A., Funayama, R., Nakayama, K., Ogawa, T., Abe, T., Katori, Y., Igarashi, K.Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat due to the lack of molecularly targeted drugs with high anti-tumor efficacy and safety. To investigate the involvement of the transcription factor BACH1, which is known to promote the metastasis of various cancers, in the malignant properties of HNSCC cells, we examined the effects of BACH1 depletion with short interfering RNAs in human HNSCC cell lines. We found that knockdown of BACH1 induced cell death due to depletion of […]
- by Suhail, Y., Du, W., Afzal, J., Wagner, G., KshitizStromal regulation of cancer dissemination is now well recognized, however causal stromal genes and factors have yet not been identified. Placental invasion into endometrial stroma phenotypically is similar to cancer dissemination. There are also vast differences in the extent of placental invasion across mammals, with human pregnancies at the higher extreme end of invasiveness. We have previously demonstrated that epitheliochorial species, characterized by non-invasive placentation, have acquired stromal resistance to placental invasion, correlating with low cancer malignancy rates. Similarly, decidualization […]
- by CAI, Z., Xu, J., Li, Y., Wang, Z., Li, Q., Liu, A., Sheng, J., Yang, L., Dong, G.Background: Lynch Syndrome (LS) is an autosomal dominant disease characterized by germline heterozygous mutations in DNA mismatch repair (MMR) genes. High-risk LS patients may proceed to colorectal cancer (CRC). However, the drivers or biomarkers of LS benign colon tissue approaching malignant CRC are not completely understood. The similarity and difference between LS-related and nonLS-related CRC are also not well interrogated (LS-CRC vs. nonLS-CRC). This study aimed to understand the cellular changes during malignant transition in LS. Methods: Single-cell RNA sequencing […]
- by Negrea, G. G., Balacescu, L., Pavel, O., Rauca, V., Dume, B., Licarete, E., Patras, L., Banciu, M., Sesarman, A.Chemoresistance continues to remain a significant barrier to the effective treatment of various cancers, including melanoma. Previous studies, including our own, have demonstrated the limited efficacy of doxorubicin (DOX) against melanoma cells and tumors, both in vitro and in vivo, primarily due to acquired chemoresistance. The lack of favorable outcomes in metastatic melanoma patients treated with liposomal DOX highlights the need to identify early DOX-induced resistance biomarkers and develop combination strategies to improve efficacy. This study explores early adaptive responses […]
- by Yang, Y., Shi, J., Yang, Y., Liu, S., Li, Y., Feng, L., Yan, R., Yao, J., Chen, L., Ding, L., Zhang, Z., Feng, H., Chen, H., Lu, Q., Yan, T., Yan, Z., Chandrakesan, P., Qu, D., Du, J., Cao, Z., Peng, J., Weygant, N.The Wnt signaling pathway is a key driver of stemness and progression which contributes to mortality in colorectal cancer (CRC). R-spondins bind to LGR receptors to inhibit ubiquitin E3 ligases, thus protecting Frizzled from degradation and activating downstream Wnt signaling. Herein, we identify Palmdelphin (PALMD) as a functional marker of CRC stem cells, interspersed between intestinal and colonic crypt base epithelial cells, and predictive of aggressive CMS4 CRC and poor survival. Gene knockdown and overexpression studies revealed that PALMD initiates […]
- by Liu, S., Pecar, G., Cao, Y., Chen, F., Wedn, A., Atkinson, J. M., Hooda, J., Oesterreich, S., Lee, A. V.Brain metastases (BrM) occur in 10-15% of patients with estrogen receptor (ER)-positive breast cancer, and remain a significant clinical challenge. While current therapeutic paradigms, including surgical resection and systemic therapy, have efficacy in the management of BrM from ER+BC, median overall survival following the diagnosis of BrM is approximately 18 months. The limited efficacy of current therapies, along with a relative paucity of therapeutic options, highlight the urgent clinical need to identify druggable targets for BrM from ER+BC. We previously […]
- by Vidal-Sabanes, M., Bonifaci, N., Navaridas, R., Egea, J., Encinas, M., Rodriguez-Barrueco, R., Silva, J. M., Matias-Guiu, X., Llobet-Navas, D., Dolcet, X.Endometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGF{beta}-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the […]
- by Shamekhi, T., Zeng, B., Sun, C. X., Daniel, P., Lim Kam Sian, T. C. C., Goncalves, G., Huang, G., Fahimi, F., Selvakumar, N., Tanuwidjaya, E., Woodhouse, I., Kritzer, B., Schittenhelm, R. B., Mazzieri, R., Cain, J. E., Nazarin, J., Hansford, J. R., Firestein, R., Dolcetti, R., Faridi, P.Background: Diffuse midline gliomas (DMGs) are among the most aggressive paediatric brain tumours, with the pathognomonic H3K27M mutation present in over 80% of cases. This mutation drives epigenetic dysregulation and transcriptional reprogramming, yet its impact on the tumour antigenic landscape remains poorly understood. Given the low mutational burden of DMG, an expanded search beyond neoantigens to include epigenetically dysregulated tumour-associated antigens (TAAs) is critical for advancing antigen-specific immunotherapies. Methods: To assess how H3K27M influences antigenic landscape of DMG, we performed […]
- by Refet-Mollof, E., Chermat, R., Lafontaine, J., Ye, R. Z., Gervais, T., Wong, P.Hypoxia influences the biology and response of cancers. No user-friendly device allows the study of hypoxia on highly-controlled clinically-relevant tumor models. Here, we describe how hypoxic-core (HyCo) spheroids generated using our unique non-perfused microfluidic device recapitulate key clinical hallmarks of hypoxia in vitro. Our PDMS-made system can generate up to 240 spheroids naturally exhibiting a diffusion-driven hypoxic core in only 4 days, here from two sarcoma cell lines. Compared to smaller normoxic spheroids from the same cell lines, known hypoxia-related […]
- by Caggiano, E., Lopez-Hernandez, A., Waldrop, T., Liu, K., Gatica-Gutierrez, H., Vargas-Hernandez, S., Mims, N., Acevedo-Diaz, A., Velasquez, B., Neil, D., Aguilar, E., Meyer, M., Echeverria, G. V., Koong, A., Spiotto, M., Gustavsson, A.-K., Schueler, E. V.Purpose: Ultra-high dose rate (>40 Gy/s, FLASH) radiation therapy (RT) provides equivalent tumor control while reducing normal tissue toxicity relative to conventional dose rate (CONV) RT. However, the mechanisms underlying the observed FLASH effect are unknown. We hypothesized that the preservation of mitochondrial integrity in nontumorigenic cells by FLASH RT could be a key factor in reducing normal tissue toxicity and improving overall treatment outcomes. Methods: We examined mitochondrial health and function after CONV and FLASH in vitro, ex vivo, […]
- by Cimino, P. J., Keiser, D. J., Parrish, A. G., Holland, E. C., Szulzewsky, F.YAP1 gene fusions are found in a multitude of human tumors, are potent oncogenic drivers, and are the likely initiating tumorigenic events in these tumors. We and others have previously shown that a YAP1 fusion proteins exert TEAD-dependent oncogenic YAP1 activity that is resistant to inhibitory Hippo pathway signaling. However, the contributions of the C-terminal fusion partners to the oncogenic functions of YAP1 fusion proteins are understudied. Here, we used the RCAS/tv-a system to express eight different YAP1 gene fusions […]
- by Gamble, A., Ward, T. A., Wheeler, O. P., Jones, C. M., Bennett, L., Vernon, E. G., Thandendran, V., Morris, J. P., Ceppi, I., Halder, S., Borello, D., Walker, T. D., Rajan, J., Dunphy, G., Cejka, P., Unterholzner, L., Staples, C. J.Replication stress is a key driver of DNA damage and genome instability. Replication stress-induced fork remodelling generates a new DNA end that is vulnerable to the action of nucleases, and which is protected by a range of factors including the canonical tumour suppressors BRCA1 and BRCA2. Here we report that replication stress drives elevated production of cytokines and chemokines in the absence of DNA damage. The DNA sensor IFI16 binds nascent DNA at stalled replication forks and signals via the […]
- by Mason, M. S., Morales Murillo, H., Dudek, M. G., Maher, S. E., Franco, S. J.The leading cause of brain cancer-related death in children is diffuse midline glioma (DMG). A particularly aggressive DMG subtype is pediatric diffuse intrinsic pontine glioma (DIPG), which is caused by the histone mutation H3.3K27M. Because of its diffuse growth and location in a critical brainstem structure, therapeutic options are limited and DIPG is considered universally fatal. Lack of appropriate animal models has hindered our understanding of the developmental origins and progression of DIPG, which in turn has limited development of […]
- by Guo, W., Luan, J., Huang, X., Leon, D., Good, J., Nicholson, B., Izumchenko, E., Rosenberg, A. J., Agrawal, N., Bertacchi, B., Bolotin, D., Gunzer, M., Ballesteros, I., Hidalgo, A., Miao, Y. P.The abundant accumulation of neutrophils in various solid cancers has been well recognized, but the functions of tumor-associated neutrophils (TANs) remain controversial. TANs have long been believed to be immune suppressive and have thus been referred to as myeloid-derived suppressor cells. However, effective tumor control induced by immunotherapy was recently found to be associated with strong neutrophil signatures. These seemingly contradictory findings highlight the unexpected degree of plasticity and heterogeneity unique to TANs. How the cellular plasticity and functional heterogeneity […]
- by Porto, S. A., Birdsall, G. A., Harper, N. W., Honeywell, M. E., Lee, M. J.EGFR is a proto-oncogene that is mutationally activated in a variety of cancers. Small molecule inhibitors targeting EGFR can be effective in slowing the progression of disease, and in some settings these drugs even cause dramatic tumor regression. However, responses to EGFR inhibitors are rarely durable, and the mechanisms contributing to response variation remain unclear. In particular, several distinct mechanisms have been proposed for how EGFR inhibition activates cell death, and a consensus has yet to emerge. In this study, […]
- by Beals, N., Ramirez, C., Koide, A., Hauser, A. D., Davies, F., Koide, S., Morgan, G., Bar-Sagi, D.Roughly 50% of newly diagnosed multiple myeloma (MM) cases harbor KRAS (25%) or NRAS (24%) mutations with an even greater frequency of these mutations observed at relapse. By and large, mutant RAS-driven MM is more resistant to existing therapies including proteasome inhibitors, immunomodulator drugs (IMiDs), and monoclonal anti-CD38 antibodies. In the present study, we demonstrate that mutant RAS-dependent macropinocytosis (MP) can be leveraged for selective delivery of a monobody-drug conjugate (MDC) to mutant RAS MM cells. This MDC delivery platform […]
- by Kraft, A., Toenz, A., Schlaepfer, F., Ronner, M., Orlowski, V., Kirschner, M. B., Bein, J., Wild, P. J., Boeva, V., Opitz, I., Meerang, M.Pleural mesothelioma (PM) is a rare yet aggressive and heterogeneous cancer type with very poor survival rates. Due to its long latency period and nonspecific symptoms, the disease is usually detected at advanced stages, limiting available treatment options and leading to poor survival rates. So far, the disease can only be confirmed through invasive thoracoscopic biopsy, and proposed circulating protein biomarkers lack sensitivity and specificity, highlighting the urgent need for novel approaches. In our previous work, we characterized the transcriptomic […]
- by Schurer, A., Ilyas, H., Maron, M. I., Hegde, S., Leyden, M. R., Roy, I., Hyka, R., Dada, L., Shabanowitz, J., Hunt, D., Angeles, E., Morell, V., Lorton, B. M., Glushakow-Smith, S., Borger, D. K., Wang, Y., Miles, L. A., Belizaire, R., Kitamura, S., Gritsman, K., Shechter, D.NPM1-mutated acute myeloid leukemia (AML) is defined by aberrant cytoplasmic localization of the mutant NPM1c protein, and therapeutic strategies targeting this specific disease remain limited. Here, we identify TTLL4, a mono-glutamate glutamyltransferase, as a selective vulnerability in NPM1c AML. TTLL4 catalyzes post-translational hyper-glutamylation of NPM1c at E126, stabilizes its cytoplasmic localization and promotes a differentiation block in leukemic cells. Multiple genetic TTLL4 inactivation approaches in human NPM1c-mutant cell lines reduce NPM1c glutamylation, trigger myeloid differentiation, and impair proliferation. Transcriptomic analyses […]
- by Dominguez-Garcia, S., Rodriguez, J., Julia, M., Coursier, D., Perez-Lopez, C., Carnicero, P., Villar, A. V., von Kriegsheim, A., Calvo, F.Cancers adapt proteostasis to cope with the burden of misfolded proteins, stabilize key signalling nodes and sustain their malignant behaviour. Tumour stroma is subjected to similar stresses, but how they influence its aberrant status remains unclear. We show that tumour stroma presents consistent upregulation of target genes associated to the major misfolding regulator HSP90 in cancer-associated fibroblasts (CAFs), and that HSP90 is required for CAFs to remodel the extracellular matrix (ECM) and promote cancer cell motility and growth. Mechanistically, HSP90 […]
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