Oncology
Abstract
Radiotherapy (RT) is a central treatment for prostate cancer (PCa), acting by inducing DNA double-strand breaks (DSBs). Tumor ability to repair these breaks limits RT efficacy, making DSB repair inhibitors potential radiosensitizers. Therefore, tumor-specific radiosensitization strategies are critically needed for PCa. Approximately 50% of PCa cases harbor the TMPRSS2-ERG gene fusion, leading to overexpression of the ERG transcription factor (ERG+). We demonstrate that ERG+ tumors shift DSB repair toward the PARP1-dependent end-joining (PARP1-EJ) pathway. Proteomic and western blot analyses revealed elevated PARP1, XRCC1, and LIG3 in ERG+ cells. PARP inhibition with olaparib increased residual γH2AX/53BP1 foci post-irradiation in ERG+ cells, indicating enhanced radiosensitization. In tissue-slice-cultures (TSCs) from 53 tumors of 40 high-risk PCa patients, olaparib selectively increased H2AX/53BP1 foci selectively in ERG+ samples. ERG+ patient-derived organoids also showed significantly delayed growth and survival when treated with olaparib plus RT compared to either treatment alone. Interestingly, ERG-negative cells within ERG+ TSCs were similarly radiosensitized by olaparib, likely through bystander effect, with residual 53BP1 foci levels comparable to ERG+ cells, confirmed by medium exchange experiments. These findings suggest that ERG expression promotes dependency on PARP1-EJ, rendering ERG+ PCa more susceptible to PARP inhibition. Combining PARP inhibitors with RT may offer a tumor-selective radiosensitization for ERG+ PCa patients.
Authors
Sabrina Köcher, Mohamed E. Elsesy, Ayham Moustafa, Wahid Mohammadi, Adriana Perugachi Heinsohn, Yamini Nagaraj, Su Jung Oh-Hohenhorst, Jan Hahn, Bente Siebels, Thomas Mair, Susanne Burdak-Rothkamm, Pierre Tennstedt, Ronald Simon, Tobias Lange, Derya Tilki, Thorsten Frenzel, Tobias Maurer, Cordula Petersen, Hartmut Schlüter, Carsten Bokemeyer, Gunhild von Amsberg, Kai Rothkamm, Wael Y. Mansour
Abstract
Chordoma are rare malignant osseous neoplasms with a striking rate of recurrence. Primary chordomas typically originate from embryonic notochord remnants, whereas recurrent chordomas usually stem from tumor cells infiltrating bone or cartilage post-surgery. Clinically, the recurrent chordomas exhibit stiffer extracellular microenvironment (ECM) than primary tumors. Intriguingly, this study identified cytoskeleton rearrangement, stress fiber reorganization, enhanced stemness, and Notch signaling activation in recurrent chordoma tissues or cell lines surviving stiff substrates, indicating the critical roles of mechanical remodeling and tumor stemness in stiffness-resistance. We propose a novel recurrence model where tumor cells experience mechanoadaptive organization to resist stiff microenvironment-induced cell death. O-GlcNAcylation of Notch1 intracellular domain (NICD1) is central to this process. Mechanistically, the stiff ECM-driven ligand-independent phosphorylation of EPHA2 sequentially activates LYN kinase, and subsequently triggers OGT activity by phosphorylating Y989 and Y418, the newly revealed critical residues for OGT glycosyltransferase activity; this induces NICD1 O-GlcNAcylation at T2063, T2090, and S2162, specifically promoting transcription of mechanical and stemness-related genes. MIR31 deletion upregulates LYN, enhancing stiffness perception and tipping the balance toward O-GlcNAc addition to NICD1, finally resulting in mechanoadaptation- and tumor stemness-driven recurrence. Consequently, MIR31 deletion is a potential biomarker for recurrence and patient stratification in Notch- or OGT-targeted therapies.
Authors
Chengjie Lian, Weiyan Peng, Peiqiang Su, Yan Ye, Jialing Liu, Dongsheng Huang, Xuejuan Sun, Yi Pu, Zhiheng Liao, Xudong Wang, Zhu Qiu, Shanshan Wu, Lei Liu
Abstract
Programmed cell death 1 ligand 1–targeted (PD-L1–targeted) immune checkpoint inhibitors are revolutionizing cancer therapy. However, strategies to induce endogenous PD-L1 degradation represent an emerging therapeutic paradigm. Here, we identified proanthocyanidins (PC) as a potent inducer of PD-L1 degradation through an endoplasmic reticulum–associated degradation (ERAD) mechanism. Mechanistically, PC exerted dual effects: First, it targeted and stabilized LKB1 to activate AMPK in tumor cells, subsequently inducing the phosphorylation of PD-L1 at Ser195 — a disruption that in turn impaired glycosylation of PD-L1 and promoted its retention in the ER. Second, PC directly bound to the E3 ubiquitin ligase SYVN1 to increase its protein stability, which strengthened PD-L1–SYVN1 binding, thereby accelerating K48-linked ubiquitination and proteasomal degradation of ER-retained PD-L1. This cascade culminated in the activation of CD8+ T cell–dominated antitumor immune responses, accompanied by suppression of myeloid-derived suppressor cells and regulatory T cells. In preclinical models of lung and colorectal cancer, PC exhibited synergistic antitumor efficacy when combined with anti–cytotoxic T lymphocyte antigen 4 (anti–CTLA-4) antibodies. Notably, PC also potently inhibited the progression of azoxymethane/dextran sodium sulfate–induced orthotopic colorectal cancer in mice. Collectively, our findings unveil an antitumor mechanism of PC, establishing this small-molecule compound as an ERAD pathway–exploiting immune checkpoint modulator with promising translational potential for cancer therapy.
Authors
Mengting Xu, Xuwen Lin, Hanchi Xu, Hongmei Hu, Xinying Xue, Qing Zhang, Dianping Yu, Saisai Tian, Mei Xie, Linyang Li, Xiaoyu Tao, Xinru Li, Simeng Li, Shize Xie, Yating Tian, Xia Liu, Hanchen Xu, Qun Wang, Weidong Zhang, Sanhong Liu
Abstract
Metastatic progression in aggressive breast cancer (BC) depends on a tightly controlled vesicular recycling network regulated by RAB11, a small guanosine triphosphate enzyme (GTPase). In a cohort of more than 1,000 patients with BC, we identified SH3BP5L as the most highly expressed guanine nucleotide exchange factor (GEF) for RAB11A. High SH3BP5L expression marked an advanced tumor stage, distant metastasis, and poor prognosis, with significant associations in human epidermal growth factor receptor 2–positive (HER2+) and triple-negative breast cancer (TNBC). Using Förster resonance energy transfer (FRET) sensors and artificial intelligence– (AI-assisted) microscopy, we showed that cargo delivery to the plasma membrane required SH3BP5L-dependent activation of RAB11A and assembly of a complex with the anterograde motor KIF5B. This trafficking governed key metastatic features of TNBC, including β1 integrin recycling and α3β1 integrin surface exposure. Inhibition of SH3BP5L or its GEF activity reduced cell spreading in zebrafish and lung metastasis in mouse models, revealing a previously unidentified driver of BC dissemination and a potential therapeutic vulnerability.
Authors
Huayi Li, Maria Chiara De Santis, Francesco A. Tucci, Daniela Tosoni, Ping Zhang, Meredith L. Jenkins, Giulia Villari, Maria Grazia Filippone, Elisa Guerrera, Simone Tealdi, Luca Gozzelino, Federico Gulluni, Lorenzo Prever, Cristina Zanini, Marco Forni, Irene Franco, Miriam Martini, John E. Burke, Guido Serini, Carlo Cosimo Campa, Salvatore Pece, Jean Piero Margaria, Emilio Hirsch
Abstract
TFE3 translocation renal cell carcinoma (tRCC), an aggressive kidney cancer driven by TFE3 gene fusions, is frequently misdiagnosed owing to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays that detect tumor DNA via somatic mutations or copy number alterations are unsuitable for tRCC since it often lacks recurrent genetic alterations and because fusion breakpoints are highly variable between patients. We reasoned that epigenomic profiling could more effectively detect tRCC because the driver fusion constitutes an oncogenic transcription factor that alters gene regulation. By defining a TFE3-driven epigenomic signature in tRCC cell lines and detecting it in patient plasma using ChIP-seq, we distinguished tRCC from clear-cell RCC (AUC = 0.86) and samples of individuals without evidence of cancer (AUC = 0.92) at low tumor fractions (<1%). This work establishes a framework for noninvasive epigenomic detection, diagnosis, and monitoring of tRCC, with implications for other mutationally quiet, fusion-driven cancers.
Authors
Simon Garinet, Karl Semaan, Jiao Li, Ze Zhang, Prathyusha Konda, Ananthan Sadagopan, John Canniff, Noa Phillips, Kelly Klega, Medha Pandey, Hunter Savignano, Matthew P. Davidsohn, Kevin Lyons, Alessandro Medda, Prateek Khanna, Mingkee Achom, Brad J. Fortunato, Rashad Nawfal, Razane El Hajj Chehade, Jillian O’Toole, Jack Horst, Dory Freeman, Rachel Trowbridge, Cindy H. Chau, William D. Figg, Jacob E. Berchuck, Brian D. Crompton, Ji-Heui Seo, Toni K. Choueiri, Matthew L. Freedman, Sylvan C. Baca, Srinivas R. Viswanathan
Abstract
MAP kinase kinase kinase kinase (MAP4K) family kinases are key kinases for T-cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T-cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, single-cell RNA sequencing (scRNA-seq), and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced forkhead box protein P3 (FOXP3) gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and the sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was significantly improved in T-Map4k2 cKO mice, Treg-specific Map4k2-deficient mice, adoptively transferred chimeric mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of human pancreatic patients showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of antitumor immunity.
Authors
Huai-Chia Chuang, Chia-Wen Wang, Chia-Hsin Hsueh, Yu-Zhi Xiao, Ching-Yi Tsai, Pu-Ming Hsu, Evelyn L. Tan, Hsien-Yi Chiu, Tse-Hua Tan
Abstract
Glioblastoma (GBM) is a highly lethal brain tumor with limited treatment options and resistance to immune checkpoint inhibitors due to its immunosuppressive tumor microenvironment (TME). Here, we identify OLIG2 as a key regulator of immune evasion in GBM stem-like cells, inhibiting CD8+ T cell-dependent antitumor immunity, while promoting pro-tumor macrophages polarization. Mechanistically, OLIG2 recruits HDAC7 to repress CXCL10 transcription, inducing STAT3 activation in tumor-associated macrophages (TAMs) and decreasing CD8+ T cell infiltration and activation. Genetic deletion of OLIG2 significantly increases CXCL10 secretion, shifting TAMs toward an anti-tumor phenotype and enhancing CD8+ T cell activities. Furthermore, upregulated OLIG2 expression is correlated to resistance to immune checkpoint inhibitors (ICIs) in GBM patients. OLIG2 inhibition by either genetic deficiency or pharmacological targeting with CT-179 sensitizes GBM tumors to anti-PD-L1 therapy, enhancing antitumor immune responses and prolonging survival. Our findings reveal OLIG2+ glioma stem-like cells as critical mediators of immune evasion and identify the OLIG2/HDAC7/CXCL10 axis as a potential therapeutic target to enhance immune checkpoint inhibitors efficacy and to improve immunotherapy outcomes in aggressive GBM.
Authors
Xinchun Zhang, Jinjiang Xue, Cunyan Zhao, Chenqiuyue Zeng, Jiacheng Zhong, Gangfeng Yu, Xi Yang, Yao Ling, Dazhen Li, Jiaxiao Yang, Yun Xiu, Hongda Li, Shiyuan Hong, Liangjun Qiao, Song Chen, Q. Richard Lu, Yaqi Deng, Zhaohua Tang, Fanghui Lu
PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARP inhibitors (PARPi) may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restore natural killer (NK) cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlates with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells binds to ANXA6 and activates the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocks the FPR1-AKT signaling and diminishes the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolongs survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.
Authors
Zheng Chao, Le Li, Xiaodong Hao, Hao Peng, Yanan Wang, Chunyu Zhang, Xiangdong Guo, Peikun Liu, Sheng Ma, Junbiao Zhang, Guanyu Qu, Yuzheng Peng, Zhengping Wei, Jing Luo, Bo Liu, Peixiang Lan, Zhihua Wang
Abstract
Authors
Johnathan R. Kent, Keene L. Abbott, Rachel Nordgren, Amy Deik, Nupur K. Das, Millenia Waite, Tenzin Kunchok, Anna Shevzov-Zebrun, Nathaniel Christiansen, Amir Sadek, Darren S. Bryan, Mark K. Ferguson, Jessica S. Donington, Alexander Muir, Yatrik M. Shah, Clary B. Clish, Matthew G. Vander Heiden, Maria Lucia L. Madariaga, Peggy P. Hsu
Abstract
Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.
Authors
Parasvi S Patel, Jacob P. Matson, Xiaojuan Ran, Marcello Stanzione, Ajinkya S. Kawale, Mingchao Wang, Sneha Saxena, Conrad Sander, Jacquelyn Curtis, Jessica L. Hopkins, Edmond Wong, Ryan B. Corcoran, Daniel A. Haber, Nicholas J. Dyson, Shyamala Maheswaran, Lee Zou
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)