Oncology
Abstract
Lineage plasticity, or transdifferentiation, is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Lineage plasticity is characterized by loss of AR signaling and epithelial differentiation, along with activation of stemness-associated pathways, epithelial-mesenchymal transition (EMT), or alternative differentiation programs such as neuroendocrine prostate cancer (NEPC). Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Using multi-omic profiling of TP53/RB1 loss prostate cancer models, we identified alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. Importantly, many pathways activated upon TP53/RB1 loss could be blocked through BET bromodomain inhibition. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with restraining lineage plasticity. Combined BET bromodomain and DNA methyltransferase (DNMT) inhibition was more effective than single agent treatment in suppressing growth of TP53/RB1 loss models exhibiting a stem-like or NEPC program. This was partly explained by abrogation of discrete lineage plasticity pathways modulated by each agent. Altogether, our work suggests combined BET bromodomain and DNMT inhibition is a promising therapeutic approach for prostate tumors exhibiting lineage plasticity.
Authors
William K. Storck, Diana Flores, Anbarasu Kumaraswamy, Zhi Duan, Shrabastee Chakraborty, Chao Zhang, Eva Rodansky, Dhruv Khokhani, Olivia A. Swaim, Karan Bedi, Raymond G. Cavalcante, Canping Chen, Faming Zhao, Ya-Mei Hu, Zheng Xia, Ryan J. Rebernick, Marcin Cieslik, Rahul Mannan, Somnath Mahapatra, Arul M. Chinnaiyan, Aaron M. Udager, Joshua A. Kuleape, Catherine R. Alumkal, Hannah N. Beck, Peter S. Nelson, Colm Morrissey, Michael C. Haffner, Leigh Ellis, Yuzhuo Wang, Joel A. Yates, Joshi J. Alumkal
Abstract
To identify therapeutic targets limiting glioblastoma invasion, we applied druggable genome CRISPRi screens and multiomic analysis to patient-derived glioblastoma cells in micro-dissectible biomimetic 3D hydrogels that permitted separation and analysis of core versus invasive fractions. Of 2,550 genes screened, 12 encoded druggable targets whose suppression limited invasion, of which AURKB (encoding aurora kinase B) and ACP1 (encoding low molecular weight protein tyrosine phosphatase, LMW-PTP) were validated in neurosphere assays and in vivo. Proximity labeling identified cortactin as a link between LMW-PTP and aurora B, and we observed that cortactin underwent serine phosphorylation by aurora B and tyrosine dephosphorylation by LMW-PTP. Targeting ACP1 or AURKB via CRISPRi or inhibitors in culture and in vivo shifted the cortactin phosphorylation balance in glioblastoma, reducing levels of cortactin and the actin-related protein 2/3 (Arp2/3) complex that mediates cortactin-induced actin stabilization, thereby reducing actin-cortactin-Arp2/3 colocalization and subsequent actin polymerization. AURKB or ACP1 targeting shifted actin from cytoplasm to the nucleus, reducing mesenchymal gene expression. Biophysical analysis implicated AURKB in glioblastoma cell adhesion and stiffness needed for initial migration and ACP1 in mechanical stress resistance required for later migration. These findings revealed a targetable axis balancing kinase and phosphatase activities to regulate actin polymerization during glioblastoma invasion.
Authors
Mufeng Hu, Anna Weldy, Isabella M. Lovalvo, Erin A. Akins, Saket Jain, Alexander Chang, Ankita Sati, Meeki Lad, Austin Lui, Akhil Rajidi, Ameya Kothekar, Erika A. Ding, Juan A. Oses Prieto, Pablo Estevez, Alma L. Burlingame, Sanjay Kumar, Manish K. Aghi
Abstract
Metastatic prostate cancer is a clinically and molecularly heterogeneous disease. Under the selective pressure of androgen receptor (AR)–directed therapies, resistant phenotypes frequently emerge, posing significant diagnostic and therapeutic challenges. Neuroendocrine prostate cancer (NEPC) is a clinically important phenotype characterized by lineage plasticity, neuroendocrine features, visceral metastases and poor prognosis. Accurately diagnosing NEPC remains difficult due to its histologic and molecular complexity but has high clinical relevance. In this study, we developed a deep learning model that leverages interpretable cellular features to improve feature extraction from H&E-stained tissue sections (NEURAL-PC). By incorporating a multiple instance learning (MIL) framework, NEURAL-PC enables robust NEPC classification solely from H&E tumor images, achieving an area under the receiver operating characteristic curve (AUROC) of 0.921 in independent external validation. In addition to its diagnostic utility, NEURAL-PC provides prognostic information that enables further subclassification of advanced prostate cancer across diverse datasets supporting its strong prognostic value and generalizability. Broadly, our work highlights a hybrid approach that integrates features across different domains, offering a promising strategy for developing reliable deep learning tools in pathology. Built on this framework, NEURAL-PC represents an extensively validated diagnostic and prognostic model for advanced prostate cancer.
Authors
Zhijun Chen, Erolcan Sayar, Daniela Guevara, Helen Richards, Haoyue Zhang, Radhika A. Patel, Agnes C. Gawne, Lucas J. Liu, Ilsa Coleman, Ruth Dumpit, Colm Morrissey, Michael T. Schweizer, Ruben Raychaudhuri, Laura S. Graham, Evan Y. Yu, Heather H. Cheng, Chien-Kuang C. Ding, Yuzhuo Wang, Peter Choyke, Baris Turkbey, Chantal Chanel-Vos, Christina Fedorov, John R. Otilano III, Troy Kane, Jyothi Manohar, Michael Sigouros, Jones T. Nauseef, Ana Molina, David Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Himisha P. Beltran, Ruth Etzioni, Peter S. Nelson, Rama Soundararajan, Ana M. Aparicio, Cora N. Sternberg, Michael C. Haffner, Stephanie A. Harmon
Abstract
BACKGROUND. Prior studies identified plasma proteins associated with chronic graft-versus-host disease (cGVHD). The goal of this cross-sectional study was to evaluate whether plasma biomarkers were associated with specific organ manifestations to help guide treatment choice. METHODS. Plasma proteins were measured in patients with cGVHD (n = 695) from Chronic GVHD Consortium studies. Correlations of plasma protein levels with individual organ involvement were tested with p≤0.05 considered significant after Benjamini-Hochberg adjustment and adjustment for five baseline clinical variables. RESULTS. Median time from cGVHD diagnosis to blood draw was 0.9 months (IQR 0.1–9.5). Donors were 50% HLA-matched unrelated, 32% matched related and the remainder were umbilical cord blood, haploidentical or mismatched unrelated donors. Methotrexate and calcineurin inhibitor acute GVHD (aGVHD) prophylaxis was used in 53% of patients. Overall, 326 (47%) had moderate and 244 (35%) had severe cGVHD with the following organ involvement at time of blood draw: skin (67%), mouth (60%), eye (49%), joint (34%), GI (31%), lung (23%), and liver (17%). After adjustment for batch effects and patient and transplant characteristics, fourteen plasma proteins were associated with organ involvement with independent AUCs of 0.7-0.8. All organs except eye were associated with at least one biomarker. However, no combination of plasma proteins improved model fit after adjusting for patient and transplant clinical variables. CONCLUSION. Correlations between plasma proteins and organ involvement were identified but are not actionable. Our future investigations will focus on more granular and immediately proximal determinants of cGVHD biology in both blood and tissue.
Authors
Stephanie J. Lee, Corey Cutler, Ningxin Ma, Timothy W. Randolph, George L. Chen, Joseph Pidala, Betty K. Hamilton, Carrie L. Kitko, Sally Arai, Najla El Jurdi, Lynn Onstad, Motoko Koyama, Catherine J. Lee, Sophie Paczesny, Geoffrey R. Hill
Abstract
Authors
Tara L Hogenson, William Phillips, Merih D Toruner, Zachry S. Poshusta, Luciana Almada, Hao Xie, Ryan M. Carr, Jenny J. Li, David L. Marks, Renzo Vera, Erik Jessen, Michael Barrett, Joleen Hubbard, Travis E. Grotz, Martin E. Fernandez-Zapico
Abstract
Undifferentiated pleomorphic sarcoma (UPS) is one of the most common adult soft tissue sarcomas (STS), yet therapeutic progress remains limited due to the absence of recurrent oncogenic driver mutations. To identify tumor suppressors contributing to UPS pathogenesis, we performed a customized in vivo CRISPR/Cas9 screen in mice. This approach identified BRCA1-associated protein 1 (BAP1) as a potent tumor suppressor in STS. Integrative analyses using RNA sequencing, multiplex immunohistochemistry, and flow cytometry revealed that Bap1-deficient sarcomas exhibited a markedly immunosuppressive tumor microenvironment. Consistent with these findings, BAP1 protein expression was reduced in human UPS, whereas polo-like kinase 1 (PLK1) expression was elevated. Functional studies demonstrated that PLK1 was required for the growth and survival of Bap1-deficient sarcomas. Pharmacologic inhibition of PLK1 with volasertib significantly suppressed tumor growth in both syngeneic and autochthonous mouse models. Moreover, combining PLK1 inhibition with anti-PD-1 therapy enhanced tumor control and improved survival compared with either treatment alone. Together, these results identify PLK1 as a potential therapeutic vulnerability in BAP1-deficient sarcomas and support further evaluation of combined PLK1 inhibition and immune checkpoint blockade as a treatment strategy for a subset of STS.
Authors
Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Zhaoyu Sun, Melissa J. Kasiewicz, Yaping Wu, Brian Piening, John T. Welle, Wesley K. Rosales, Venkatesh Rajamanickam, So Young Kim, Eric S. Xu, Lixia Luo, Yan Ma, Rutulkumar Patel, Ziqiang Zhang, Brady Bernard, William L. Redmond, Walter J. Urba, R. Bryan Bell, David G. Kirsch
Abstract
Selecting appropriate preclinical models is fundamental for translational oncology, yet a large-scale, multi-omic quantitative comparison of their similarity to primary human tumors is lacking. To address this, we integrated transcriptomic, proteomic, and genomic profiles from over 10,000 primary tumors from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), alongside 4,000 preclinical models. Using a robust computational framework, we revealed a clear hierarchy of transcriptomic and proteomic similarity to patient tumors: patient-derived xenografts (PDXs) > patient-derived organoids (PDOs) = PDX-derived organoids (PDXOs) > cell lines. We also quantified high molecular conservation (Pearson correlation coefficient = 0.96) across paired in vitro to in vivo platform (organoids to PDX) transitions. Furthermore, genomic analysis demonstrated that whole-exome sequencing (WES) outperforms RNA sequencing (RNA-Seq) in detecting DNA variants, and it identified a clonal complexity hierarchy (cell lines > PDXOs > PDXs > PDOs) reflecting the impact of passaging history on intra-tumor heterogeneity. Ultimately, this study delivers a comprehensive quantitative benchmark, establishing a population-level hierarchy of molecular similarity between preclinical models and primary tumors, and providing a data-driven reference for model selection. These findings offer a data-driven framework for selecting models that balance biological representativeness with experimental practicality.
Authors
Zixuan Xie, Jia Xue, Binchen Mao, Hengyuan Liu, Wubin Qian, Jingjing Wang, Xiaobo Chen, Sheng Guo
Abstract
Authors
Erin M. Dickey, Harper M. Marsh, Camilla Rydberg-Millrud, Haleh Amirian, Karthik Rajkumar, Manan Patel, Andrew Adams, Anuroop Allena, Kevin Van der Jeught, Nipun Merchant, Peter J. Hosein, Anna Bianchi, David Liberg, Jashodeep Datta
Abstract
While Wilms tumors commonly arise from renal precursor cells and maintain features of the developing kidney, recent studies have demonstrated significant genetic, histologic, and molecular heterogeneity. To further investigate tumor variability as well as unifying features in tumor biology, we performed single nuclei RNA-sequencing (snRNA-seq) on treatment naïve, favorable histology Wilms tumors utilizing a reference atlas established from tumor-adjacent kidney samples and fetal kidney. Transcriptional profiles of blastemal, stromal, and epithelial components were correlated with tumor histology and demonstrate developmental-lineage plasticity, with PAX2 and PAX8 expression normally restricted to the nephron lineage of the fetal kidney found to be expressed in tumor stroma, as well as the stromal marker POSTN identified in tumor blastema. Further analyses of the blastema show shared transcriptional features with the differentiation trajectory of “uninduced” to “early differentiating” fetal nephron progenitor cells as well as aberrant expression of stromal signatures. A number of pathways from fetal nephron progenitors were maintained in the blastema, including regulation of stem cell maintainence and axonogenesis, whereas other pathways appear enriched in specific tumor samples, demonstrating the ability of snRNA-seq to identify both unifiying transcriptional signatures and uncover distinct molecular targets in signaling pathways and/or biological drivers of Wilms tumorigenesis.
Authors
Mike Adam, Keri A. Drake, Naomi Pode-Shakked, Katherine VandenHeuvel, Steve Potter, James Geller
Abstract
Tumor cells are constantly confronted with nutrient deprivation; however, the effect of serum starvation on the remodeling of endosomal compartments and extracellular vesicles (EVs) in tumor cells remains unclear. Here, we found that serum starvation pronouncedly promotes multivesicular body (MVB) biogenesis, EV formation, and cargo selection. Specifically, by generating a constitutively active Rab5Q79L mutant to induce the enlargement of MVB, we revealed for the first time to our knowledge that ANXA3 is sorted into intraluminal vesicles (ILVs) of MVB. Mechanistically, we confirmed that serum starvation regulates the endosomal sorting complex required for transport–associated (ESCRT-associated) protein ALG-2 interacting protein X (ALIX), which recruits ESCRT-III to MVB and binds to annexin A3 (ANXA3) to mediate its sorting into ILVs of MVB. Our study highlights that serum starvation promotes an ALIX-dependent ESCRT-III recruitment pathway, which loads protumor ANXA3 cargo to exert a profound effect on tumor progression.
Authors
Xueqiang Peng, Jiaxing Liu, Guolong Zeng, Yafei Xiao, Zhixiong Hao, Guangpeng He, Hongyuan Jin, Yu Gao, Shilei Tang, Shibo Wei, Yan Li, Yifan Yu, Liang Yang, Hangyu Li
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