Oncology
Abstract
Human carcinomas often gain aggressive characteristics and escape cell-type specific treatment regimens through cryptic shifts in lineage states. However, the underlying mechanisms that govern lineage plasticity in carcinomas are undefined. Here in this study, we found that PAX5, a neural/lymphatic transcription factor, contributed to neuroendocrine (NE) lineage transition. PAX5 was highly expressed in aggressive human NE carcinoma cells and tissues but not in non-NE cancer cells and tissues. Deletion of Pax5 in Rb1fl/fl;Trp53fl/fl mice caused a reduction of tumor vessels, loss of NE morphologic features and decreased expression of ASCL1, NCAM, and SYP, whereas ectopic expression of PAX5 in CC10-rtTA;TetO-hEGFRex19del/T790M mice adenocarcinomas and in LNCAP prostate cancer xenografts induces an angiogenic microenvironment and NE morphology. Importantly, antiangiogenic drugs reduced NE features of Rb1fl/fl;Trp53fl/fl tumors and blocked PAX5-induced NE transformation. These studies demonstrate an essential role of angiogenic microenvironment in transition/maintenance of NE lineage, suggesting that targeting PAX5 and its downstream signaling may modulate lineage transitions responsible for treatment failure in both SCNCs and adenocarcinomas.
Authors
Ailing Wu, Yujie Hao, Xuemiao Yan, Junrong Liu, Lin Wang, Yan Jin, Wenxu Liu, Xiyue Chen, Yuan Jiang, Luc Girard, Zhiqun Shang, Jun Yan, Zhenfa Zhang, Wenchen Gong, Yuanjie Niu, Benjamin J. Drapkin, John D. Minna, Lance S. Terada, Zhenyi Ma, Zhe Liu
Abstract
Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. A similar mechanism occurred after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrated that dipeptides containing essential amino acids activated the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored resistant lymphoma sensitivity to 6MP. Strikingly, resistant lymphomas, but not primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, in culture and in vivo. We extended these findings in human lymphoma biopsies, which revealed increased SLC15A3 expression following antimetabolite therapy. Together, our study uncovered a metabolic adaptation that fuels cancer resistance to nucleotide deficiency and positions the mTORC1 inhibitor, rapamycin, as a potential therapeutic strategy for transforming the management of chemotherapy-resistant lymphomas.
Authors
Haojun Yang, Vincenzo Andrea Zingaro, Kevin Boardman, Ashish Noronha, Ekin Guney, Lingru Xue, Saishma Hoigebazar, Isabelle Liu, Sohit Miglani, Siyu Chen, Hieu Vu, Kwun Wah Wen, Hao G. Nguyen, Hani Goodarzi, Ralph J. DeBerardinis, Davide Ruggero
Abstract
Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we showed that hypoxia-inducing anti-VEGF therapy upregulated programmed cell death ligand 1 (PD-L1), yet failed to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggered epithelial osteopontin (SPP1) production, which recruited monocytes and skewed macrophages toward M2 states, suppressing T cell cytotoxicity. Pharmacological SPP1 depletion impeded the development of hypoxia, reduced M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenics and anti–PD-L1. Genetic dissection — tumor-epithelial Spp1-KO grafts and bone marrow chimeras generated by lethal irradiation and reconstitution with Spp1–/– or WT hematopoietic donors — showed that myeloid SPP1 contributed only marginally compared with epithelial SPP1. These findings identified SPP1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contributed to a comprehensive model of antiangiogenic resistance, and supported SPP1-targeted strategies to personalize immunotherapy and antiangiogenic therapy according to tumor hypoxia.
Authors
Jose Luis Ruiz-Sepulveda, Maria J. Bueno, Silvana Mouron, Veronica Jimenez-Renard, Manuel Muñoz, Manuel Moradiellos, Leonardo D. Garma, Luis García-Jimeno, Adam W. Watson, Ghassan Mouneimne, Solip Park, Rebeca Jimeno, Miguel Quintela-Fandino
Abstract
Opioids are essential analgesics for managing severe pain but can paradoxically increase pain sensitivity (hyperalgesia) and diminish analgesic efficacy (tolerance). Hyperactivity of NMDA-type glutamate receptors (NMDARs) at primary afferent terminals in the spinal cord contributes to both phenomena; however, the underlying signaling mechanisms remain unclear. Here, we report that morphine administration in rats promoted the translocation of monomeric BRAF, an oncogenic kinase, from the dorsal root ganglion (DRG) to spinal cord synaptosomes, leading to increased MEK-ERK phosphorylation at nociceptor central terminals. BRAF physically interacted with NMDARs in both rat and human spinal cords. Inhibition of BRAF activity with vemurafenib reversed morphine-induced NMDAR phosphorylation and synaptic localization of α2δ-1–bound NMDARs. Vemurafenib also abolished morphine-induced presynaptic NMDAR hyperactivity in spinal dorsal horn neurons. Correspondingly, conditional Braf knockout in DRG neurons normalized morphine-enhanced NMDAR phosphorylation, synaptic trafficking of α2δ-1–bound NMDARs, and NMDAR hyperactivity in the spinal cord. Furthermore, pharmacological inhibition of BRAF or MEK, or Braf deletion in DRG neurons, enhanced morphine analgesia while mitigated morphine-induced hyperalgesia and tolerance. These findings identify BRAF overactivity at nociceptor central terminals as a key mediator of opioid-induced NMDAR hyperactivity. Clinically approved BRAF inhibitors could be repurposed to enhance opioid analgesia while minimizing adverse effects.
Authors
Daozhong Jin, Hong Chen, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan
Abstract
Our research uncovers a new role for ATR in responding to extracellular matrix (ECM) stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2 which promotes β-catenin nuclear translocation and EMT. ATM mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103+ dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal to epithelial transition to enhance anti-tumor immunity and mitigate metastases. Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor, Berzosertib, in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR targeted therapy may be optimized by considering both DNA damage dependent and EMT inducing effects of ATR.
Authors
Xinyi Tu, Xiangyu Zeng, Yaoliang Sun, Yaobin Ouyang, Lingling Zhu, Ping Yin, Kevin D. Pavelko, Roberto A. Leon-Ferre, Yanxia Jiang, Haidong Dong, Jodi M. Carter, Shouhai Zhu, Jann N. Sarkaria, Liewei Wang, Jinzhou Huang, Kuntian Luo, Yiqun Han, Zheming Wu, Zhenkun Lou, Robert W. Mutter
Abstract
ATR inhibition is under evaluation for treatment of high-grade serous ovarian cancer (HGSOC) to reverse acquired resistance to poly (ADP-ribose) polymerase (PARP) inhibition and to exacerbate chemotherapy-induced replicative stress. Here, we define PTEN deficiency as a predictive biomarker for response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared to PTEN-proficient cells, PTEN-deficient cells are prone to (1) uncoupling of DNA polymerase and helicase activities, leading to excessive single-stranded DNA and replication stress; (2) cytoplasmic sequestration of CHK1, compromising cell cycle checkpoint control with reduced compensatory effects by ATM and DNA-PK, leading to mitotic catastrophe; and (3) reduced RAD51 recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses demonstrate that patients with HGSOC expressing low PTEN levels experience greater clinical benefit on ATR inhibitor-based trials than those with high levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.
Authors
Jie Hao, Bose Kochupurakkal, Timothy B. Branigan, Ozge Sezin Somuncu, Renyan Liu, Heta Jadhav, Alexandre Andre B.A. da Costa, Yuqing Jiao, Jenny Z. Yu, David B. Martignetti, Golbahar Sadatrezaei, Sirisha Mukkavalli, Prafulla C. Gokhale, Su-Chun Cheng, Steven J. Skates, Dimitrios Nasioudis, Panagiotis A. Konstantinopoulos, Joyce F. Liu, Stephanie L. Gaillard, Robert L. Giuntoli II, Lainie P. Martin, Janos L. Tanyi, Nawar Latif, Ian S. Heller, Fiona Simpkins, Kalindi Parmar, Alan D. D'Andrea, Geoffrey I. Shapiro
Abstract
YAP and TAZ, key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEAD transcription factors, making the TEAD-YAP/TAZ complex a promising therapeutic target. Using translational mouse models, we showed here that sustained systemic YAP/TAZ depletion caused severe side effects. These could be avoided through pulsed inhibition, which effectively suppressed tumor growth, even at advanced stages. We identified Tgfb2 as a critical YAP/TAZ target gene for tumor formation and demonstrated that YAP/TAZ drove T cell exclusion via activation of tissue remodeling genes. Consequently, YAP/TAZ inhibition enhanced immune cell infiltration. However, infiltrating T cells rapidly underwent exhaustion. Combining YAP/TAZ inhibition with immune checkpoint blockade (ICB) reversed this exhaustion and sensitized resistant tumors to immunotherapy. This combination reshaped the tumor microenvironment to support immune cell infiltration and activation, representing a therapeutic strategy that maximizes anti-tumor immunity while minimizing toxicity.
Authors
Marco Jessen, KyungMok Kim, Marie Tollot-Wegner, Anita Cindric Vranesic, Cagla Dönmez, Celina Junker, Tina Lehmann, Advitiya Khandelwal, Yuliya Kurlishchuk, Tom Hünniger, Christin Ritter, Evaristo Di Napoli, Shyam Murali, Konrad Bücking, Viktoria Haug, Sabine Muth, Tracy T. Tang, Andreas Rosenwald, Markus Radsak, Donato Inverso, Tanja Deckert-Gaudig, Volker Deckert, Orlando Paciello, Björn von Eyss
Abstract
MDM2 is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53 activation induces MDM2 transcription, creating a feedback loop that blunts inhibitor efficacy. We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling. In vivo, KT-253 produced deep and durable tumor regressions, including complete responses in patient-derived xenograft models. Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.
Authors
Varsha Ananthapadmanabhan, Simone Bruno, Leonard Vonk, Yu-Chen Cheng, Abeba Teshager, Benjamin K. Eschle, Charles L. Howarth, Joana S. Rodrigues, Julia Schnabel, Ananya Kodali, Prafulla C. Gokhale, Rujuta Kshirsagar, Susanne B. Breitkopf, Kirti Sharma, Joao A. Paulo, Yvonne Li, Andrew D. Cherniack, Franziska Michor, Yogesh Chutake, Joyoti Dey, James A. DeCaprio
Abstract
BACKGROUND. B cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma (MM), yet its whole-body in vivo distribution and role in disease assessment remain incompletely defined. We aimed to evaluate the safety, diagnostic performance, and clinical utility of a novel BCMA-targeted PET tracer, 68Ga-PFBC01, in patients with plasma cell disorders. METHODS. We conducted a single-center, prospective, single-arm phase I trial (ClinicalTrials.gov NCT06717113). Fifty patients underwent 68Ga-PFBC01 PET/CT, including 40 with paired 18F-FDG PET/CT for head-to-head comparison. Primary outcomes included diagnostic performance (sensitivity, specificity, PPV, NPV, and inter-reader agreement). Secondary outcomes included correlations with clinical biomarkers, treatment response assessment, impact on clinical decision-making, and safety. RESULTS.68Ga-PFBC01 PET/CT demonstrated superior diagnostic performance compared with 18F-FDG PET/CT (sensitivity 96.9% vs 84.6%; specificity 71.4% vs 60.0%). Quantitative PET-derived tumor burden correlated with M protein (R = 0.325, P = 0.026), free light chains (R = 0.340–0.437, P ≤ 0.015), soluble BCMA (R = 0.433, P = 0.050), and bone marrow plasma cells (R = 0.682, P < 0.001). Imaging findings altered clinical management in multiple cases, enabling both therapy escalation and de-escalation. Blood-pool uptake strongly correlated with soluble BCMA (R = 0.899, P < 0.001) and overall disease burden (R = 0.736, P < 0.001). No serious tracer-related adverse events were observed; two patients (4%) experienced mild events. CONCLUSION.68Ga-PFBC01 PET/CT provides biologically specific, whole-body assessment of MM, outperforming 18F-FDG and enabling integrated evaluation of tumor burden and systemic disease activity, with direct implications for clinical decision-making. TRIAL REGISTRATION. ClinicalTrials.gov NCT06717113. FUNDING. National Natural Science Foundation of China (82472018, 82402320) to Prof. Lei Kang, 82402320 to Dr. Tianyao Wang); Beijing Nova Program (20240484725) to Prof. Lei Kang; National High Level Hospital Clinical Research Funding (Interdisciplinary Research Project of Peking University First Hospital, 2024IR07, Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2025CX38, 2024CX18) to Prof. Lei Kang.
Authors
Tingfei Gu, Zhao Chen, Bo Tang, Tianyao Wang, Qi Yang, Huihui Liu, Zeyin Liang, Qian Wang, Yang Zhang, Yuhua Sun, Mingyi Di, Tingting Yuan, Yongkang Qiu, Yimeng Du, Lele Song, Shengnan Wu, Wei Wang, Xiaojie Xu, Yujun Dong, Lei Kang
Abstract
Glioblastoma is a fatal primary malignant brain tumor, with an average survival of 15 months despite surgical resection, chemotherapy, and radiation therapy. Due to the concurrent deregulation of numerous genes in glioblastoma, molecular monotherapies have not improved clinical outcomes. Evidence suggests that targeting multiple deregulated molecules is essential for better therapies; however, this is limited by the lack of suitable drugs and increased toxicity of combination therapies. To address this, we hypothesized that miRNAs, small gene-regulatory RNAs that suppress mRNA, could simultaneously inhibit multiple deregulated genes in glioblastoma, and be used for more effective therapies. We identified regulatory miRNAs — those that target several deregulated genes in glioblastoma — using a combination of PAR-CLIP screening, TCGA data analyses and an algorithm to rank target importance and miRNA therapeutic potential. We selected two tumor suppressor miRNAs, miR-340 and miR-382, and one oncogenic miRNA, miR-17 and showed that they target critical glioblastoma pathways and alter cell growth, survival, invasion, and in vivo tumor growth. We developed and successfully applied a miRNA therapeutic delivery approach using Brain Penetrating Nanoparticles combined with MRI-guided focused ultrasound and microbubbles, to inhibit established tumor growth and to extend animal survival. This strategy offers a promising approach for translating miRNA-based therapies into clinical trials for glioblastoma and other cancers.
Authors
Shekhar Saha, Ying Zhang, Myron K. Gibert Jr., Collin Dube, Farina Hanif, Elizabeth Qian Xu Mulcahy, Sylwia Bednarek, Yunan Sun, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Ahsan H. Polash, Haolin Li, Kadie Hudson, Manikarna Dinda, Tapas Saha, Matthew McCord, Fadila Guessous, Nichola Cruickshanks, Rossymar Rivera Colon, Lily Dell'Olio, Rajitha Anbu, Wenjie Liu, Songy Choi, Benjamin Kefas, Pankaj Kumar, Alexander L. Klibanov, David Schiff, Jung Soo Suk, Justin Hanes, Jamie Mata, Markus Hafner, Roger Abounader
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)