Jul 2026· Journal of Clinical Investigation· 0 citations
Medicine
TL;DR
It is found that PAX5, a neural/lymphatic transcription factor, contributed to neuroendocrine (NE) lineage transition, and targeting PAX5 and its downstream signaling may modulate lineage transitions responsible for treatment failure in both SCNCs and adenocarcinomas.
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.
Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-resistant subtype that arises from adenocarcinoma through lineage plasticity; however, the molecular mechanisms driving this transition remain incompletely defined. Insulinoma-associated protein 1 (INSM1), a zinc-finger transcription factor and established neuroendocrine lineage marker, has been implicated in a variety of neuroendocrine malignancies, yet its functional contribution to NEPC progression is not well understood. In this study, we demonstrate that INSM1 is consistently upregulated across NEPC patient tumors and experimental models, including both ASCL1⁺ and NEUROD1⁺ molecular subtypes, as revealed by integrated bulk and single-cell transcriptomic analyses. Functional studies revealed that INSM1 is sufficient to induce and necessary to maintain neuroendocrine lineage programs in prostate cancer, as overexpression promoted and depletion suppressed neuroendocrine-associated transcriptional networks. Mechanistically, pro-neural transcription factors, including ASCL1, NEUROD1, NEUROG3, and MYCN, directly or indirectly activate INSM1 expression, positioning it as a critical downstream effector of neuroendocrine lineage specification. Therapeutically, we identify homo-harringtonine (HHT), an FDA-approved protein synthesis inhibitor, as a potent suppressor of INSM1. HHT selectively reduces viability of INSM1-high NEPC cells at nanomolar concentrations, promotes ubiquitin-mediated degradation of INSM1, and significantly inhibits tumor growth in vivo. Notably, INSM1 depletion further enhances cellular sensitivity to HHT treatment. Collectively, our findings establish INSM1 as a key regulator of neuroendocrine plasticity and a promising therapeutic vulnerability in NEPC, providing a rationale for targeting INSM1 to suppress tumor progression.
Chiachen Chen, Siyuan Cheng, Lin Li et al.· bioRxiv· 0 citations
Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of advanced prostate cancer characterized by poor prognosis and limited treatment options. Enzalutamide, an androgen receptor (AR) pathway inhibitor, is a standard second-line therapy for prostate adenocarcinoma (PrAd). However, enzalutamide resistance (EnzR) promotes not only neuroendocrine differentiation (NED) but also the induction of stemness-associated programs in PrAd cells. We identified the de novo DNA methyltransferase DNMT3B as a stemness-related gene upregulated in EnzR-PrAd cells and found that its expression is further significantly elevated in NEPC compared with PrAd. Our studies reveal that DNMT3B is a critical driver of NEPC development by coordinating the regulation of neuroendocrine and stemness transcriptional networks. Genetic inhibition of DNMT3B suppresses NEPC cell proliferation by impairing cell-cycle progression and triggering apoptosis both in vitro and in vivo. DNMT3B loss altered NED-associated, stemness, and epithelial-associated genes. We further uncover a reciprocal regulatory relationship between DNMT3B and the neuroendocrine transcriptional repressor REST. Using a human prostate cell transformation model that recapitulates NEPC evolution, we demonstrate that DNMT3B is required for both the initiation and maintenance of the NEPC phenotype. Finally, pharmacologic inhibition of DNMT3B with the selective inhibitor Nanaomycin A reduces NEPC tumor growth and suppresses NED and stemness marker expression without apparent acute toxicity in vivo. Implications: DNMT3B drives therapy-induced lineage plasticity in prostate cancer, and its inhibition suppresses NEPC growth and differentiation, highlighting it as a promising therapeutic target for treatment-resistant disease.
Yunsol Jo, H. Jung, Ziqin Wang et al.· Molecular Cancer Research· 0 citations
This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Jia Li, Jinling Li, Yuechao Zhao et al.· Frontiers in Immunology· 0 citations
Cancer-associated fibroblasts (CAFs) represent a major structural component of solid tumors and play crucial roles in cancer progression and drug resistance. However, their developmental origin, differentiation trajectory, and therapeutic potential remain poorly defined. Using advanced approaches—including inducible genetic lineage tracing, single-cell RNA sequencing, and spatial transcriptomic profiling—we identified a population of Cd34+Pi16+ fibroblast progenitors (Cd34+ CAFs) in both melanoma and gastric cancer. We delineated their differentiation trajectory toward Acta2+ CAFs, driven by the upregulation of the transcription factor Foxs1. This work establishes the developmental origin of Acta2+ CAFs and experimentally validates the Cd34+ to Acta2+ transition. By reverse-matching the transcriptional signatures of Acta2+ CAF differentiation with the CMap/LINCS L1000 drug perturbation database, we identified four small-molecule candidates predicted to inhibit tumor-induced Foxs1 upregulation. These compounds effectively suppressed Cd34+ CAF differentiation, maintaining the progenitor-like Cd34+ state. Collectively, this study proposes a novel antitumor strategy that targets CAF lineage development to restrain tumor progression. A comprehensive atlas of CD34⁺ fibroblast progenitors within the tumor microenvironment was generated using single-cell sequencing and lineage tracing, delineating their differentiation trajectory toward myofibroblasts and identifying potential therapeutic targets to block this transition. In situ sequencing reveals that CD34⁺Pi16⁺ CAFs originate adjacent to blood vessels, suggesting a vascular adventitial progenitor origin. Dual-recombinase lineage tracing combined with diphtheria toxin ablation demonstrates that CD34⁺Pi16⁺ cells are an essential source of tumor myofibroblasts required for tumor growth. Foxs1 directly binds the α-SMA promoter to drive CD34⁺ to Acta2⁺ CAF conversion, and its knockdown suppresses tumor growth in vivo. Machine learning-based screening of CMap/LINCS L1000 identifies disulfiram and three other compounds that block CAF differentiation and restrain tumor progression. Pharmacological intervention preserves the CD34⁺Pi16⁺ progenitor state, with single-cell sequencing confirming that WH-4-023 reverses CAF phenotypic transition. In situ sequencing reveals that CD34⁺Pi16⁺ CAFs originate adjacent to blood vessels, suggesting a vascular adventitial progenitor origin. Dual-recombinase lineage tracing combined with diphtheria toxin ablation demonstrates that CD34⁺Pi16⁺ cells are an essential source of tumor myofibroblasts required for tumor growth. Foxs1 directly binds the α-SMA promoter to drive CD34⁺ to Acta2⁺ CAF conversion, and its knockdown suppresses tumor growth in vivo. Machine learning-based screening of CMap/LINCS L1000 identifies disulfiram and three other compounds that block CAF differentiation and restrain tumor progression. Pharmacological intervention preserves the CD34⁺Pi16⁺ progenitor state, with single-cell sequencing confirming that WH-4-023 reverses CAF phenotypic transition. A comprehensive atlas of CD34⁺ fibroblast progenitors within the tumor microenvironment was generated using single-cell sequencing and lineage tracing, delineating their differentiation trajectory toward myofibroblasts and identifying potential therapeutic targets to block this transition.
Junyao Yang, Ting Chen, Run Zhang et al.· EMBO Molecular Medicine· 0 citations
Choroid Plexus tumors constitute 10–20% of brain tumors in infancy. Among these, Choroid Plexus Carcinomas (CPC) are highly aggressive and result in poor survival. Details on tumor initiation and oncogenic events remain largely unknown, aside from a high prevalence of TP53 mutations and marked chromosomal instability. We generated hGFAP-cre::lsl-MYCN::lsl-Gli2(N)::Tp53fl/fl mice with recombination activity from embryonic day 13.5 onwards in CNS cells, leading to MYCN and Gli2 activation as well as TP53 inactivation. 84% of the mice developed ventricular tumors within 18 days of life, resembling human CPCs in histology and marker expression. We performed histological and molecular characterization of the resulting tumors and treated tumor cells in vitro. We demonstrate that aberrant Sonic Hedgehog (SHH) signaling during embryonic Choroid Plexus (CP) development triggers a dedifferentiation cascade that reverts mature epithelium to a progenitor-like state. Spatial transcriptomic analysis identifies a distinct cellular hierarchy, where differentiated plexus cells shed their secretory identity to adopt malignant progenitor states. This transformation is accompanied by a transition from multiciliated epithelial cells expressing mature, secretory CP markers to highly proliferative, monociliated progenitors expressing SOX2. This malignant reprogramming activates embryonic developmental programs and induces a critical dependency on cell cycle and DNA repair pathways. Consequently, we identify that these tumor cells cultivated in vitro are vulnerable to ATR and CDK inhibition.
Levke-Sophie Peter, L. Altendorf, K. Hack et al.· Acta Neuropathologica Commun...· 0 citations
Lung adenocarcinoma (LUAD) shows extensive lineage plasticity and early metastatic dissemination, but the oncogenic events that actively drive these processes remain poorly defined. Here, we identify coordinated PRKCI and ECT2 copy number gain, present in approximately 30% of human LUADs, as a driver of developmental reprogramming and metastasis. Using a genetically engineered mouse model that recapitulates PRKCI-ECT2 gain in Kras/Trp53-driven LUAD, we show that elevated PKCι-ECT2 signaling rewires tumor trajectory in a cell-of-origin-dependent manner. Alveolar type II cell-derived tumors dedifferentiate into a distal SOX9high progenitor-like state associated with aggressive growth and liver metastasis, whereas club cell-derived tumors transition into a foregut SOX2high progenitor-like state that supports lineage infidelity and histological transformation. Human LUAD analyses support these progenitor programs as clinically relevant features of PRKCI-ECT2 gain.
Duy T Nguyen, Kayleah M Meneses, Cheng Zhang et al.· Cell Reports· 0 citations