Genetic Phenomena Commons^™

Statistical Identification Of Cell Type-Specific Spatially Variable Genes In Spatial Transcriptomics, Lulu Shang, Peijun Wu, Xiang Zhou

Faculty, Staff and Student Publications

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real …

Urine Proteomics Defines An Immune Checkpoint-Associated Nephritis Signature, James P Long, Shailbala Singh, Yanlan Dong, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy is required to differentiate ICI-AIN from other causes of acute kidney injury (AKI). However, this invasive approach can lead to morbidity, delayed glucocorticoid treatment for patients with AIN, and unnecessarily prolonged suspension of ICI therapy in non-AIN patients. Delayed or incorrect diagnosis of ICI-AIN is particularly detrimental, as over 50% of patients are at risk of permanent renal damage. Thus, there is an urgent need for non-invasive biomarkers that can rapidly and accurately distinguish …

Joint Fluid Multi-Omics Improves Diagnostic Confidence During Evaluation Of Children With Presumed Septic Arthritis, Yolanda Peña-López, Naureen G Tareen, Bo Zhang, Indu Raman, Carlos A Arana, Chengsong Zhu, Yang Liu, Pratibha Selvakumar, Nicolai S C Van Oers, Simrat Morris, Lora V Hooper, Lawson A B Copley, Prithvi Raj

Faculty, Staff and Student Publications

Background: An accurate diagnosis of septic versus reactive or autoimmune arthritis remains clinically challenging. A multi-omics strategy comprising metagenomic and proteomic technologies were undertaken for children diagnosed with presumed septic arthritis to advance clinical diagnoses and care for affected individuals.

Methods: Twelve children with suspected septic arthritis were prospectively enrolled to compare standard of care tests with a rapid multi-omics approach. The multi-omics combined bacterial 16S rRNA metagenomics, single cell transcriptomics, and proteomics on knee joint fluid specimens. The diagnostic value of the multi-omics was ascertained relative to standard of care culture and PCR-negative results.

Results: Ten children with suspected …

Spatial Transcriptome Reveals Histology-Correlated Immune Signature Learnt By Deep Learning Attention Mechanism On H&E-Stained Images For Ovarian Cancer Prognosis, Chun Wai Ng, Kwong-Kwok Wong, Barrett C Lawson, Sammy Ferri-Borgogno, Samuel C Mok

Faculty, Staff and Student Publications

Background: The ability to predict the prognosis of patients with ovarian cancer can greatly improve disease management. However, the knowledge on the mechanism of the prediction is limited. We sought to deconvolute the attention feature learnt by a deep learning convolutional neural networks trained with whole-slide images (WSIs) of hematoxylin-and-eosin (H&E)-stained tumor samples using spatial transcriptomic data.

Methods: In this study, 773 WSIs of H&E-stained tumor sections from 335 patients with treatment naïve high-grade serous ovarian cancer who were included in The Cancer Genome Atlas (TCGA) Pan-Cancer study were used to train, and validate, and to test a ResNet101 CNN …

Inhibition Of Vascular Smooth Muscle Cell Perk/Atf4 Er Stress Signaling Protects Against Abdominal Aortic Aneurysms, Brennan Callow, Xiaobing He, Nicholas Juriga, Kevin D Mangum, Amrita Joshi, Xianying Xing, Andrea Obi, Abhijnan Chattopadhyay, Dianna M Milewicz, Mary X O'Riordan, Johann Gudjonsson, Katherine Gallagher, Frank M Davis

Faculty, Staff and Student Publications

Abdominal aortic aneurysms (AAA) are a life-threatening cardiovascular disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by vascular smooth muscle cell (VSMC) dysfunction and apoptosis, for which the mechanisms regulating loss of VSMCs within the aortic wall remain poorly defined. Using single-cell RNA-Seq of human AAA tissues, we identified increased activation of the endoplasmic reticulum stress response pathway, PERK/eIF2α/ATF4, in aortic VSMCs resulting in upregulation of an apoptotic cellular response. Mechanistically, we reported that aberrant TNF-α activity within the aortic wall induces VSMC ATF4 activation through the …

Cd5-Positive High-Grade B-Cell Lymphoma With Myc, Bcl2, And Bcl6 Rearrangements, Wei J Wang, Zhihong Hu

Faculty, Staff and Student Publications

No abstract provided.

Optimized Methods To Quantify Tumor Treating Fields (Ttfields)-Induced Permeabilization Of Glioblastoma Cell Membranes, Melisa Martinez-Paniagua, Sabbir Khan, Nikita W Henning, Sri Vaishnavi Konagalla, Chirag B Patel

Faculty, Staff and Student Publications

Glioblastoma (GBM) is a lethal primary brain cancer with a 5.6% five-year survival rate. Tumor treating fields (TTFields) are alternating low-intensity electric fields that have demonstrated a GBM patient survival benefit. We previously reported that 0.5-24 h of TTFields exposure resulted in an increased uptake of FITC-dextran fluorescent probes (4-20 kDa) in human GBM cells. However, this approach, in which a fluorescence plate-based detector is used to evaluate cells attached to glass coverslips, cannot distinguish FITC-dextran uptake in live vs. dead cells. The goal of the study was to report the optimization and validation of two independent methods to quantify …

Stratification System With Dual Human Endogenous Retroviruses For Predicting Immunotherapy Efficacy In Metastatic Clear-Cell Renal Cell Carcinoma, Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Virginie Verkarre, Cheng-Ming Sun, Wenxuan Cheng, Li Xu, Fangrong Yan, Salma Kotti, Wolf Hervé Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. While the dysregulation of ERV transcription has been linked to immune cell infiltration in various cancers, its relationship with immune checkpoint inhibitor (ICI) response in solid tumors, particularly metastatic clear-cell renal cell carcinoma (ccRCC), remains inadequately explored.

Methods: This study analyzed patients with metastatic ccRCC from two prospective clinical trials, encompassing 181 patients receiving nivolumab in the CheckMate trials (-009 to -010 and -025) and 48 patients treated with the ipilimumab-nivolumab combination in the BIONIKK trial. ERV expression was quantified using the ERVmap algorithm …

A Deconvolution Framework That Uses Single-Cell Sequencing Plus A Small Benchmark Data Set For Accurate Analysis Of Cell Type Ratios In Complex Tissue Samples, Shuai Guo, Xiaoqian Liu, Xuesen Cheng, Yujie Jiang, Shuangxi Ji, Qingnan Liang, Andrew Koval, Yumei Li, Leah A Owen, Ivana K Kim, Ana Aparicio, Sanghoon Lee, Anil K Sood, Scott Kopetz, John Paul Shen, John N Weinstein, Margaret M Deangelis, Rui Chen, Wenyi Wang

Faculty, Staff and Student Publications

Bulk deconvolution with single-cell/nucleus RNA-seq data is critical for understanding heterogeneity in complex biological samples, yet the technological discrepancy across sequencing platforms limits deconvolution accuracy. To address this, we utilize an experimental design to match inter-platform biological signals, hence revealing the technological discrepancy, and then develop a deconvolution framework called DeMixSC using this well-matched, that is, benchmark, data. Built upon a novel weighted nonnegative least-squares framework, DeMixSC identifies and adjusts genes with high technological discrepancy and aligns the benchmark data with large patient cohorts of matched-tissue-type for large-scale deconvolution. Our results using two benchmark data sets of healthy retinas and …

The Association Between Thyroid Differentiation Score And Survival Outcomes In Papillary Thyroid Carcinoma, Jennifer R Wang, Mark E Zafereo, Maria E Cabanillas, Chia Chin Wu, Li Xu, Yaoyi Dai, Wenyi Wang, Stephen Y Lai, Ying Henderson, Lauren Erasmus, Michelle D Williams, Corinne Joshu, Debashree Ray

Faculty, Staff and Student Publications

Context: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in papillary thyroid carcinoma (PTC).

Objective: The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts.

Methods: Two independent cohorts of patients with PTC were used: (1) The Cancer Genome Atlas (TCGA) thyroid cancer study (N = 372), (2) MD Anderson Cancer Center (MDACC) cohort (N = 111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was …

Mitochondrial Uncouplers Inhibit Oncogenic E2f1 Activity And Prostate Cancer Growth, Ohuod Hawsawi, Weinan Xue, Tingting Du, Mengqi Guo, Xiaolin Yu, Mingyi Zhang, Paul S Hoffman, Roni Bollag, Jun Li, Jia Zhou, Hongbo Wang, Junran Zhang, Zheng Fu, Xiaoguang Chen, Chunhong Yan

Faculty, Staff and Student Publications

Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis. Consequently, NTZ/TIZ induces S-phase kinase-associated protein 2 (SKP2)-mediated G1 arrest while impeding DNA synthesis, lipogenesis, and the growth of prostate cancer cells. …

Real-Time Cbct Imaging And Motion Tracking Via A Single Arbitrarily-Angled X-Ray Projection By A Joint Dynamic Reconstruction And Motion Estimation (Dreme) Framework, Hua-Chieh Shao, Tielige Mengke, Tinsu Pan, You Zhang

Faculty, Staff and Student Publications

Objective: Real-time cone-beam computed tomography (CBCT) provides instantaneous visualization of patient anatomy for image guidance, motion tracking, and online treatment adaptation in radiotherapy. While many real-time imaging and motion tracking methods leveraged patient-specific prior information to alleviate under-sampling challenges and meet the temporal constraint (< 500 ms), the prior information can be outdated and introduce biases, thus compromising the imaging and motion tracking accuracy. To address this challenge, we developed a framework dynamic reconstruction and motion estimation (DREME) for real-time CBCT imaging and motion estimation, without relying on patient-specific prior knowledge.

Approach: DREME incorporates a deep learning-based real-time CBCT imaging and motion estimation method into a dynamic CBCT reconstruction framework. The reconstruction framework reconstructs a dynamic sequence of CBCTs in a data-driven manner from a standard pre-treatment scan, without requiring patient-specific prior knowledge. Meanwhile, a convolutional neural network-based motion encoder is jointly trained during the reconstruction …

A Dual Role Of Cohesin In Dna Dsb Repair, Michael Fedkenheuer, Yafang Shang, Seolkyoung Jung, Kevin Fedkenheuer, Solji Park, Davide Mazza, Robin Sebastian, Hiroyuki Nagashima, Dali Zong, Hua Tan, Sushil Kumar Jaiswal, Haiqing Fu, Anthony Cruz, Supriya V Vartak, Jan Wisniewski, Vittorio Sartorelli, John J O'Shea, Laura Elnitski, Andre Nussenzweig, Mirit I Aladjem, Fei-Long Meng, Rafael Casellas

Faculty, Staff and Student Publications

Cells undergo tens of thousands of DNA-damaging events each day. Defects in repairing double-stranded breaks (DSBs) can lead to genomic instability, contributing to cancer, genetic disorders, immunological diseases, and developmental defects. Cohesin, a multi-subunit protein complex, plays a crucial role in both chromosome organization and DNA repair by creating architectural loops through chromatin extrusion. However, the mechanisms by which cohesin regulates these distinct processes are not fully understood. In this study, we identify two separate roles for cohesin in DNA repair within mammalian cells. First, cohesin serves as an intrinsic architectural factor that normally prevents interactions between damaged chromatin. Second, …

A Novel Case Of Glial Transdifferentiation In Renal Medullary Carcinoma Brain Metastasis, Maria A Gubbiotti, Ian E Mccutcheon, Priya Rao, Giannicola Genovese, Linghua Wang, Artem Tarasov, Vladislav Putintsev, Amber Berlinski, Danil Stupichev, Kirill Kriukov, Suren Davitavyan, Basim Salem, Alexander Sarachakov, Dmitry Lebedev, Michael Hensley, Alexander Bagaev, Francesca Paradiso, Vladimir Kushnarev, Gleb Khegai, Nizar M Tannir, Pavlos Msaouel

Faculty, Staff and Student Publications

Renal medullary carcinoma is a rare undifferentiated tumor of the kidney associated with sickle cell trait and characterized by INI1 (SMARCB1) loss. Although metastasis to lungs, lymph nodes, and bone is commonly reported, distant spread to the central nervous system almost never occurs. Here we present an unusual case of a patient with renal medullary carcinoma with metastasis to the brain following treatment which included tazemetostat, an EZH2 inhibitor. The metastatic brain lesion harbored morphologic, immunohistochemical, and methylation profile supportive of a primary CNS phenotype with loss of the trimethylated lysine 27 residue of histone 3 while maintaining INI1 loss …

The Clinical Utility Of A Next-Generation Sequencing-Based Approach To Detecting Circulating Hpv Dna In Patients With Advanced Anal Cancer, Deepak Bhamidipati, Jay R Johnson, Kangyu Lin, Helene Pelicano, Cathy Eng, Ryan Huey, Robert A Wolff, Daniel M Halperin, Michael F Frumovitz, Ignacio I Wistuba, Dzifa Y Duose, Saradhi Mallampati, Rajyalakshmi Luthra, Van K Morris

Faculty, Staff and Student Publications

Background: To extend the practicality of liquid biopsy beyond the historical HPV circulating tumor DNA (ctDNA) assays, we evaluated the clinical relevance of a novel next-generation sequencing HPV ctDNA assay in patients with locally advanced and metastatic squamous cell cancer of the anal canal (mSCCA).

Methods: ctDNA isolated from the plasma of patients with mSCCA was sequenced using a 1.4 Mb hybrid-capture target-enrichment panel covering the whole genome sequences of all 193 HPV types. The HPV type, copy number (CN), and integration sites were determined using a bioinformatic pipeline.

Results: A total of 77 plasma samples from 28 patients with …

Utilizing Patient-Derived Xenografts To Model Precision Oncology For Biliary Tract Cancer, Timothy P Diperi, Kurt W Evans, Stephen Scott, Xiaofeng Zheng, Kaushik Varadarajan, Lawrence N Kwong, Michael Kahle, Hop S Tran Cao, Ching-Wei Tzeng, Thuy Vu, Sunhee Kim, Fei Su, Maria Gabriela Raso, Yasmeen Rizvi, Ming Zhao, Huamin Wang, Sunyoung S Lee, Timothy A Yap, Jordi Rodon, Milind Javle, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Purpose: Biliary tract cancers, which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant biliary tract cancer models that recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in biliary tract cancers to create a resource for modeling precision oncology.

Experimental design: PDXs were derived from biliary tract cancer samples collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were …

Revisiting Phosphoregulation Of Cdc25c During M-Phase Induction, Tan Tan, Chuanfen Wu, Ruoning Wang, Bih-Fang Pan, David Hawke, Fumin Yin, Zehao Su, Boye Liu, Sue-Hwa Lin, Wei Zhang, Jian Kuang

Faculty, Staff and Student Publications

Cdc25C undergoes a sudden and substantial gel mobility shift at M-phase onset, correlating with abrupt activation of both Cdc25C and Cdk1 activities. A positive feedback loop between Cdk1 and Cdc25C has been used to explain this hallmark phenomenon. Here, we demonstrate that the M-phase supershift and robust activation of Cdc25C are due to the site-comprehensive phosphorylation of its long intrinsically disordered regulatory domain without requiring Cdk1 or other major mitotic kinase activities. The phosphorylation process involves substrate-mediated assembly of phosphorylation machinery that catalyzes multisite phosphorylation continuously without substrate dissociation. In contrast to the site-comprehensive phosphorylation of Cdc25C occurring at M-phase …

Dysregulated Klf4 Expression Plays A Pivotal Role In The Pathogenesis Of Pancreatic Intraductal Papillary Mucinous Neoplasms, Xiangsheng Zuo, Liang Wang, Yi Liu, Huamin Wang, Margarete Hafley, Mihai Gagea, Ru Chen, Yun Xiong, Sheng Pan, Imad Shureiqi, Robert S Bresalier, Daoyan Wei

Faculty, Staff and Student Publications

No abstract provided.

Clinical And Molecular Characteristics Of Patients With Brain Metastasis Secondary To Pancreatic Ductal Adenocarcinoma, Mahmoud Yousef, Mark W Hurd, Abdelrahman Yousef, Ethan B Ludmir, Ashwathy B Pillai, Jennifer Peterson, Eugene J Koay, Sali Albarouki, Ching-Wei Tzeng, Rebecca Snyder, Matthew H G Katz, Huamin Wang, Michael J Overman, Anirban Maitra, Shubham Pant, Brandon G Smaglo, Robert A Wolff, James Yao, John P Shen, Dan Zhao

Faculty, Staff and Student Publications

Background: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset.

Materials and methods: The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed.

Results: Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis …

Pooled Safety Analysis And Management Of Sotorasib-Related Adverse Events In Kras G12c-Mutated Advanced Non-Small Cell Lung Cancer, Ferdinandos Skoulidis, Bob T Li, Maximilian Hochmair, Ramaswamy Govindan, Mark Vincent, Anthonie J Van Der Wekken, Noemi Reguart Aransay, Kenneth J O'Byrne, Nicolas Girard, Frank Griesinger, Makoto Nishio, Simon Häfliger, Colin Lindsay, Niels Reinmuth, Astrid Paulus, Pavlos Papakotoulas, Sang-We Kim, Carlos Gil Ferreira, Giulia Pasello, Michael Duruisseaux, Spyridon Gennatas, Anastasios Dimou, Bhakti Mehta, William Kormany, Chidozie Nduka, Brooke E Sylvester, Christine Ardito-Abraham, Yang Wang, Adrianus Johannes De Langen

Faculty, Staff and Student Publications

Introduction: We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks.

Methods: Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment.

Results: In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; …

Phase I Study Of Bms-986299, An Nlrp3 Agonist, As Monotherapy And In Combination With Nivolumab And Ipilimumab In Patients With Advanced Solid Tumors, Blessie E Nelson, Shaun O'Brien, Rahul A Sheth, David S Hong, Aung Naing, Xiaoping Zhang, Amy Xu, Lora Hamuro, Rasika Suryawanshi, Derrick Mckinley, Ruslan D Novosiadly, Sarina A Piha-Paul

Faculty, Staff and Student Publications

Purpose: BMS-986299 is a first-in-class, NOD-, LRR-, and pyrin-domain containing-3 (NLRP3) inflammasome agonist enhancing adaptive immune and T-cell memory responses.

Materials and methods: This was a phase-I (NCT03444753) study that assessed the safety and tolerability of intra-tumoral BMS-986299 monotherapy (part 1A) and in combination (part 1B) with nivolumab, and ipilimumab in advanced solid tumors. Reported here are single-center results.

Results: 36 patients were enrolled, with breast (31%), colorectal (17%), and head and neck (14%) being the more commonly enrolled cancers. Most patients (58%) had received prior immunotherapy. Therapy was well-tolerated, with G1-G2 fever (70%), neutrophilia (36%), and leukocytosis …

Nursing Knowledge In Cardio-Oncology: Results Of An International Learning Needs-Assessment Survey, Anecita Fadol, Geraldine Lee, Valerie Shelton, Kelly C Schadler, Asma Mohammed Younus, Mary Stuart, Lisa Nodzon, Edith Pituskin

Faculty, Staff and Student Publications

Background: With early detection and improvements in systemic and local therapies, millions of people are surviving cancer, but for some at a high cost. In some cancer types, cardiovascular disease now competes with recurrent cancer as the cause of death. Traditional care models, in which the cardiologist or oncologist assess patients individually, do not address complex cancer and cardiovascular needs. Nursing disciplines should be an integral part of holistic assessment in cardio-oncology care. To learn what educational needs nurses perceive important for provision of competent cardio-oncology nursing care, we undertook an international survey, aiming to understand their learning needs and …

Electrostatic Force-Enabled Microneedle Patches That Exploit Photoredox Catalysis For Transdermal Phototherapy, Hang Zhang, Wen-Chuan Xie, Yuhang Yao, Zi-Yi Tang, Wen-Xiu Ni, Bingwu Wang, Song Gao, Jonathan L Sessler, Jun-Long Zhang

Faculty, Staff and Student Publications

Microneedle patches for topical administration of photodynamic therapy (PDT) sensitizers are attractive owing to their safety, selectivity, and noninvasiveness. However, low-efficiency photosensitizer delivery coupled with the limitations of the hypoxic tumor microenvironment remains challenging. To overcome these issues, we developed an effective microneedle patch based on intermolecular electrostatic interactions within a photosensitizer matrix containing a zinc-containing porphyrin analogue, ZnBP (w). This design improved the mechanical strength of the microneedle patch and enhanced the photosensitizer loading efficiency in aqueous environments. A key feature of the system is efficient electron transfer between ZnBP (w) and NADH upon photoirradiation. Electrostatic interactions between ZnBP …

A Case For Broadening Our View Of Mechanism In Developmental Biology, B Duygu Özpolat, Swathi Arur, Mansi Srivastava

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Developmental biologists can perform studies that describe a phenomenon (descriptive work) and/or explain how the phenomenon works (mechanistic work). There is a prevalent perception that molecular/genetic explanations achieved via perturbations of gene function are the primary means of advancing mechanistic knowledge. We believe this to be a limited perspective, one that does not effectively represent the breadth of work in our field. We surveyed a representative and diverse group of colleagues to share their views on what it takes to infer mechanism. Here, we briefly examine the factors that have shaped the dominant view of mechanism, summarize responses to the …

Spatial Distribution Of Tumor Cells In Clear Cell Renal Cell Carcinoma Is Associated With Metastasis And A Matrisome Gene Expression Signature, Prahlad Bhat, Pheroze Tamboli, Kanishka Sircar, Kasthuri Kannan

Faculty, Staff and Student Publications

Background/Objectives: Predicting the behavior of clear cell renal cell carcinoma (ccRCC) is challenging using standard-of-care histopathologic examination. Indeed, pathologic RCC tumor grading, based on nuclear morphology, performs poorly in predicting outcomes of patients with International Society of Urological Pathology/World Health Organization grade 2 and 3 tumors, which account for most ccRCCs.

Methods: We applied spatial point process modeling of H&E-stained images of patients with grade 2 and grade 3 ccRCCs (n = 72) to find optimum separation into two groups.

Results: One group was associated with greater spatial randomness and clinical metastasis (p < 0.01). Notably, spatial analysis outperformed standard pathologic grading in predicting clinical metastasis. Moreover, cell-to-cell interaction distances in the metastasis-associated group were significantly greater than those in the other patient group and were also greater than expected by the random distribution of cells. Differential gene expression between the two spatially defined groups of patients revealed a matrisome signature, consistent with the extracellular matrix's crucial role in tumor invasion. The top differentially expressed genes (with a fold change > 3) stratified a larger, multi-institutional …

Zongertinib (Bi 1810631), An Irreversible Her2 Tki, Spares Egfr Signaling And Improves Therapeutic Response In Preclinical Models And Patients With Her2-Driven Cancers, Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyová, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumüller

Faculty, Staff and Student Publications

Mutations in ERBB2 (encoding HER2) occur in 2% to 4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2-mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent antitumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of …

Neutrophil Extracellular Traps Promote Pre-Metastatic Niche Formation In The Omentum By Expanding Innate-Like B Cells That Express Il-10, Wonjae Lee, Song Yi Ko, Hironari Akasaka, Melanie Weigert, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

Disseminated cancer cells in the peritoneal fluid often colonize omental fat-associated lymphoid clusters but the mechanisms are unclear. Here, we identify that innate-like B cells accumulate in the omentum of mice and women with early-stage ovarian cancer concomitantly with the extrusion of chromatin fibers by neutrophils called neutrophil extracellular traps (NETs). Studies using genetically modified NET-deficient mice, pharmacologic inhibition of NETs, and adoptive B cell transfer show that NETs induce expression of the chemoattractant CXCL13 in the pre-metastatic omentum, stimulating recruitment of peritoneal innate-like B cells that in turn promote expansion of regulatory T cells and omental metastasis through producing …

Integrating Priorities At The Intersection Of Cancer And Neuroscience, William L Hwang, Ella N Perrault, Alexander Birbrair, Brandi J Mattson, David H Gutmann, Donald J Mabbott, Edna Cukierman, Elizabeth A Repasky, Erica K Sloan, Hui Zong, Ihsan Ekin Demir, Jami L Saloman, Jeremy C Borniger, Jian Hu, Jorg Dietrich, Joshua J Breunig, Kaan Çifcibaşı, Khalil Ali Ahmad Kasm, Manuel Valiente, Max Wintermark, Munjal M Acharya, Nicole N Scheff, Nisha J D'Silva, Paola D Vermeer, Richard J Wong, Sebastien Talbot, Shawn L Hervey-Jumper, Timothy C Wang, Yi Ye, Yuan Pan, Yuri L Bunimovich, Moran Amit

Faculty, Staff and Student Publications

Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.

Nerves At Play: The Peripheral Nervous System In Extracranial Malignancies, Paola D Vermeer, Anthony C Restaino, Jeffrey L Barr, Dan Yaniv, Moran Amit

Faculty, Staff and Student Publications

The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. …

Combined Kras Inhibition And Immune Therapy Generates Durable Complete Responses In An Autochthonous Pdac Model, Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A Labella, Pingna Deng, Xiaoying Shang, Paulino Tallón De Lara, Li Cai, Shan Jiang, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in …