Oncology
Abstract
Advanced prostate cancer has increasingly developed a lethal neuroendocrine form, small cell/neuroendocrine prostate cancer (NEPC), as a consequence of the widespread use of highly potent androgen receptor signaling inhibitors in castration-resistant disease. The molecular mechanisms remain unclear and no effective therapies currently exist. We report that tryptophan hydroxylase 1 (TPH1), the enzyme responsible for peripheral serotonin biosynthesis — a neurotransmitter enriched in neuroendocrine tumors and a classical neuroendocrine biomarker — was upregulated in both de novo and therapy-induced human NEPC. TPH1 upregulation was necessary and sufficient for neuroendocrine differentiation and the NEPC phenotype through its enzymatic activity. Silencing TPH1 suppressed neuroendocrine plasticity and various aggressive behaviors of NEPC cells, including proliferation, invasion, sphere formation, and NEPC tumor xenograft growth. Mechanistically, TPH1 activated mTOR via intracellular serotonin-dependent serotonylation of mTOR at glutamine 2453, which triggered the induction of FOXM1 and E2F1 to drive NEPC differentiation and growth. Importantly, pharmacological inhibition of TPH1 using the clinically available inhibitor LX1606 effectively restricted growth and neuroendocrine marker expression in multiple NEPC cell lines and patient-derived xenografts. Collectively, these findings characterize TPH1’s contribution to NEPC and suggest TPH1 as a potential therapeutic target.
Authors
Jing Wei, Jing Wang, Jingrui Chen, Michelle Zhang, Chia-Hui Chen, Tianjie Pu, Alivia O'Brien, Sephtis Hargrove, Eva Corey, Tzu-Ping Lin, Allen C. Gao, Boyang Jason Wu
Abstract
Transport of nucleoside chemotherapeutic drugs into tumor cells is primarily accomplished through Equilibrative Nucleoside Transporter 1 (ENT1), considered to be constitutively-active, redistributing drugs across lipid bilayers via facilitated diffusion. Here we discover that ENT1 is not constitutively-active but rather requires activation of acid sphingomyelinase (ASMase) by gemcitabine, generating ceramide-rich platforms (CRPs) on external plasma membranes of endothelial and tumor cells into which ENT1 inserts, dimerizing therein to functionalize transmembrane gemcitabine transport. Whereas sarcoma cells synthesize minimal ASMase, they take up gemcitabine poorly in vitro and in murine xenografts. A strategy designed to augment gemcitabine-induced ASMase secretion into the extravascular space by ASMase-rich neo-angiogenic cells, which then targets tumor cell plasma membranes, yields “bystander” CRPs on sarcoma cells and ENT1 insertion therein, conferring markedly-enhanced gemcitabine uptake and xenograft response. Engaging this biology in a prospective Phase II clinical trial in advanced sarcoma yielded robust volumetric changes in evaluated tumors that developed early and were often durable.
Authors
Aditya Ganju, Shyam Rao, Mark A. Dickson, Robert A. Lefkowitz, Chris Thompson, Jin Cheng, Katia Manova, Adriana Haimovitz-Friedman, Gary Schwartz, Zhigang Zhang, Zvi Fuks, William D. Tap, Richard Kolesnick
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (PanNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program, and a secretory neuroendocrine program. Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in PanNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that neuronal-like-high regions localized to densely cellular tumor areas with relative depletion of stromal infiltration, whereas secretory neuroendocrine-high regions occupied fibrovascular and stromal niches enriched for endothelial, fibroblast, and myeloid populations, and associated with TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enriched for pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.
Authors
Julie Karam, Samantha E. Hoffman, Amanda Garza, Dan Gui, Hannah I. Hoffman, Breanna M. Titchen, Yutaro Tanaka, Erica Pimenta, Theodora Pappa, Laura Valderrabano, Kevin Bi, Riaz Gillani, Lauren Brais, Erin Shannon, Jason L. Hornick, Jihye Park, Jennifer Chan, Eliezer M. Van Allen
Abstract
Background: Combined checkpoint blockade (CCB) of programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4) is highly active in melanoma but limited by significant morbidity from immune-related adverse events (irAEs). Effective strategies to prevent CCB-mediated irAEs are lacking. Methods: Patients with advanced melanoma were randomly assigned to receive standard of care ipilimumab and nivolumab alone (Arm-A: ipi/nivo, n=7) or with one cycle of rituximab (Arm-B; ipi/nivo+rituximab, n=7). Results: Patients receiving ipi/nivo+rituximab experienced lower rates of > grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE-free survival compared to those in ipi/nivo arm (2-year G3-irAE-free survival 86% versus 29% (p=0.01), without adverse impact on tumor regression or survival. G3 hypersensitivity reactions to rituximab (43% in Arm-B) prompted trial closure. Rituximab depleted pre-therapy activated naïve B cells linked to autoimmunity and enhanced CCB-mediated induction of myeloid inflammation and CXCL13+ICOS+ CD4 T cells. Conclusion: B-cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk. Trial Registration: ClinicalTrials.gov NCT03719131 Funding: NIH
Authors
Kavita M. Dhodapkar, Antonio Matera, Alyssa M. Duffy, Azmain Taz, Renee Julia Manalo, Melinda Yushak, Ragini Kuchadkar, David H. Lawson, Madhav V. Dhodapkar
Abstract
Authors
Vlad Moisoiu, Roxanne Lourman, Frank Szulzewsky, Tobias Kessler, Giulio Collotta, Antonio Porro, Anne Bertolini, Franziska Singer, Patrick J. Cimino, Caroline Hertler, Wolfgang Wick, Guido Reifenberger, Eric C. Holland, Alessandro A. Sartori, Michael Weller, Hans-Georg Wirsching
Abstract
Authors
Diwakar Turaga, Chang-Ru Tsai, Yuka Morikawa, Hanna J. Tadros, Yi Zhao, Lalita Wadhwa, Iki Adachi, Xiao Li, James F. Martin
Abstract
Triple-negative breast cancer (TNBC), characterized by aggressive behavior and poor prognosis, presents a formidable clinical challenge. Despite guideline endorsement of chemoimmunotherapy as a standard treatment in TNBC, durable responses remain rare, largely due to an immunologically “cold” tumor microenvironment (TME). Through integrated analysis, we identified the F-box protein FBXW5 as a tumor-intrinsic immunosuppressive regulator, whose expression is elevated in immunologically “cold” TNBC and correlates with dismal patient survival. Genetic knockdown of murine Fbxw5 suppressed tumor growth, reinvigorated CD8+ T cell-mediated antitumor immunity, and sensitized TNBC tumors to both single-agent and combined chemo-immune therapy in preclinical models. Mechanistically, FBXW5 acts within the SKP1/CUL1/F-box protein (SCF) E3 ligase complex to bind RIGI and MDA5, promoting their K27-linked polyubiquitination and subsequent SQSTM1-mediated autophagic degradation. This process blunts cytosolic RNA sensing and type I interferon (IFN-I) signaling, thereby limiting CD8+ T cell infiltration and activation. Our findings establish FBXW5 as a master regulator of the “cold” TME, presenting a potential predictive biomarker and actionable therapeutic target for enhancing chemoimmunotherapy in TNBC.
Authors
Xin Li, Tong Chen, Wenjing Zhao, Jiaxing Li, Yifan Shang, Bing Chen, Lijuan Wang, Ning Zhang, Xiaoli Kong, Yiran Liang, Yaming Li, Chen Li, Dianwen Han, Xi Chen, Shan Jiang, Chao Yang, Dan Luo, Tingting Ma, Qifeng Yang
Abstract
Cancer hotspot mutations of unknown function often obscure the functional understanding of the molecular pathways underlying cancer formation and limit precision medicine progress. Here, we investigated unresolved driver functions of RHOA in head and neck squamous cell carcinoma (HNSCC). Our investigation reveals that RHOA E40Q is a partial loss-of-function allele which paradoxically promotes tumorigenesis only in the absence of wild-type RhoA. Therefore, mice expressing RHOA E40Q specifically in keratinocytes lacking wild-type RhoA spontaneously developed squamous cell carcinoma and showed defective hair shaft formation. Mechanistically, this is related to increased replication stress and genome instability caused by aberrant expression of cell cycle regulators and DNA repair genes, independent of the classical RhoA effectors ROCK and DIAPH. These data establish RHOA E40Q as an unusual, context-dependent oncogenic driver: a seemingly inactive variant that unleashes its tumor-promoting potential only when the wild-type allele is absent.
Authors
Justine Noujarède, Qiuyue Wang, Eleftherios Panagiotis Kokkinogenis, Yuewan Luo, Ivona Cudina, Simon Willaume, Clémence Mooser, Lap Phuoc Nguyen, Mads Frederik Poulsen, Simon Heijmerikx, Thu Han Le Phan, Xiubin He, Jesper Bøje Andersen, Claus Storgaard Sørensen, Cord Brakebusch
Abstract
Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). Although usually distinct, rare combined LUAD/SCLC tumors occur, and LUAD can transform into SCLC as a mechanism of resistance to targeted therapies, particularly in EGFR-Mutant LUADs with RB1/TP53 inactivation. Although PRC2 complex expression increases during this transformation, its functional role remains unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we found that inactivation of EED, the core PRC2 scaffolding subunit, impaired SCLC tumorigenesis and promoted LUAD histological identity likely through a NEUROD1-positive intermediate state. Mechanistically, EED loss derepressed bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes and NEUROD1. These same LUAD oncogenic signaling genes were bivalently repressed in human SCLC patient-derived xenografts, suggesting a conserved PRC2-dependent mechanism that represses LUAD oncogenic signaling and thereby supports the SCLC neuroendocrine identity. In a complementary EGFR-Mutant LUAD GEMM with Rb1 and Trp53 inactivation, EED inactivation at tumor initiation prevented the emergence of SCLC histology after EGFR oncogene withdrawal and redirected recurrent tumors toward mucinous LUAD states with reduced spontaneous metastasis. These findings identify PRC2/EED as a regulator of SCLC neuroendocrine identity and nominate pharmacologic EED inhibition for future investigation in therapy-associated LUAD-to-SCLC transformation.
Authors
Yixiang Li, Yasmin N. Laimon, Hyeonseo Cho, Marina Vivero, Gabriel Roberti de Oliveira, Maxwell D. Seager, Andrew Delcea, Varunika Savla, Yuting Chen, Yavuz T. Durmaz, Xintao Qiu, Shweta Kukreja, Rong Li, Talal El Zarif, Wesley Lu, McKayla Van Orden, Jacob E. Berchuck, Roderick T. Bronson, Shuqiang Li, Hongbin Ji, David A. Barbie, Katerina Politi, Matthew L. Freedman, Henry W. Long, Sabina Signoretti, Matthew G. Oser
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related mortality in men. Although poly(ADP-ribose) polymerase inhibitors (PARP inhibitor) are approved for mCRPC patients with homologous recombination repair (HRR) deficiencies, clinical trials combining Olaparib with PD-1/PD-L1 inhibitors have shown limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARP inhibitor in an unbiased manner, we performed bulk RNA sequencing on HRR-proficient MycCaP cells treated with the PARP inhibitor (Olaparib) versus vehicle control. Transcriptomics analysis revealed robust upregulation of CD73 (NT5E), an ectoenzyme and emerging immune checkpoint that generates extracellular adenosine, suggesting an adaptive mechanism that undermines Olaparib efficacy and promotes immunosuppression. CD73 induction by Olaparib was validated in both human and mouse prostate cancer cell lines, with more pronounced effects in HRR-compromised PTEN knockout (KO) cells. Mechanistically, olaparib-driven CD73 expression was mediated through DNA damage–activated ATR–CHEK1–IRF1 and TGF-β1–AKT signaling pathways. In parallel, Olaparib enhanced tumor immunogenicity by activating type I interferon (IFN) signaling and antigen presentation machinery. In vivo, combining olaparib with CD73 blockade significantly delayed tumor growth, improved T-cell infiltration, and augmented CD8⁺ T-cell effector function across HRR-proficient and PTEN KO prostate cancer models. These findings identify Olaparib-induced CD73 upregulation as an adaptive resistance mechanism and support Olaparib plus CD73 blockade as a promising therapeutic strategy for advanced prostate cancer, irrespective of HRR status.
Authors
Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)