Medical Specialties Commons^™

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8

Ceramide-Induced Endoplasmic Reticulum Stress Reveals A Targetable Vulnerability In Endocrine Therapy-Resistant Breast Cancer, Aanshi Vashi, Vipin Rawat, Fatimah Alani, Huiping Zhao, Malik Ata, Jun Qu, Rachel Schiff, Debra Tonetti, Geoffrey L Greene, Jonna Frasor, Gunes Ekin Atilla-Gokcumen, Jonathan L Coloff

Faculty, Staff and Students Publications

UNLABELLED: Despite the success of endocrine therapy (ET) in treating hormone receptor-positive breast cancer, a significant proportion of patients relapse during or after treatment, making ET resistance a major clinical challenge. Previously, we have shown that ET-resistant breast cancer cells exhibit reduced ceramide levels and an increased sensitivity to ceramide-induced cell death. In this study, we demonstrate that ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, characterized by upregulation of endoplasmic reticulum stress (EnRS) pathways. Ceramide-induced EnRS is PERK-dependent and functionally linked to cell death in multiple models of ET resistance. Using a photoactivatable ceramide probe, we identify TRAM1 …

Nf1 Loss In Estrogen Receptor-Positive Breast Cancer Induces Osteoclast Formation And Immunosuppression To Promote Bone Metastasis, Matthew J Baik, Yi-Hsuan Wu, Lauren K Somes, Andres F Mosquera Paternina, Omar A Harb, Owen A Chang, Fengshuo Liu, Matthew V Holt, Junkai Wang, Igor Bado, Hai Wang, George Miles, Zbigniew Gugala, Meenakshi Anurag, Ahmed Elkhanany, Yi Li, Valentina Hoyos, Xiang H-F Zhang, Eric C Chang

Faculty, Staff and Students Publications

Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. …

Cigarette Smoke Induces Fasn-Dependent Fatty Acid Metabolic Rewiring To Drive Bladder Cancer Progression, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, Minjae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri

Faculty, Staff and Students Publications

Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via …

Development Of A Structurally Distinct Topbp1 Inhibitor That Enhances Parp Blockade And Reverses Osimertinib Resistance, Yang Xiao, Lidija A Wilhelms Garan, Helena Folly-Kossi, Weei-Chin Lin

Faculty, Staff and Students Publications

Therapeutic resistance remains a major challenge in cancer treatment, driven by compensatory signaling and stress response pathways that sustain tumor survival. Topoisomerase IIβ-binding protein 1 (TopBP1), a multifunctional scaffold protein with nine BRCT domains, integrates replication stress signaling with oncogenic networks and is frequently overexpressed in aggressive cancers. Its BRCT7/8 domains mediate critical interactions with E2F1, mutant p53, MIZ1, PLK1, and CIP2A, making TopBP1-BRCT7/8 an attractive therapeutic target. Using docking-guided screening and structure-activity relationship–driven optimization, we developed CS18 as a potent and selective BRCT7/8 inhibitor that disrupts oncogenic TopBP1 complexes without interfering with DNA replication. CS18 suppresses MYC transcriptional programs, …

Unfolded Protein Response As A Therapeutic Target: 4-(Heptyloxy)Phenol Induces Programmed Cell Death In Ewing Sarcoma, Terzah M Horton, Scott R Gilbertson, Debananda Pati

Faculty, Staff and Students Publications

Ewing sarcoma is a rare and aggressive pediatric malignancy with limited therapeutic options, particularly for relapsed or refractory cases, highlighting the urgent need for innovative treatment strategies. In this study, we identify endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) as critical therapeutic vulnerabilities in Ewing sarcoma and introduce 4-(heptyloxy)phenol (AC-45594) as a novel small-molecule agent that exploits these stress pathways. AC-45594 selectively inhibited the growth of Ewing sarcoma cells among 13 cancer and 6 noncancerous cell lines, demonstrating marked tumor specificity. Structure-activity relationship studies revealed that both the phenolic hydroxyl group and an optimal alkoxy chain length …

Cost-Effectiveness Of Hes V2.0 And Galad For Hepatocellular Carcinoma Surveillance In Patients With Cirrhosis, Mary Linton B Peters, Ali Hajjar, Anthony E Samir, Leigh Anne Dageforde, Fasiha Kanwal, Jagpreet Chhatwal

Faculty, Staff and Students Publications

Background: Ultrasound-based surveillance for HCC is limited by suboptimal sensitivity and low adherence. Blood-based biomarkers are potential alternatives for routine HCC surveillance. We aimed to define optimal sensitivity, specificity, and cost parameters under which blood-based biomarkers could serve as cost-effective alternatives in patients with cirrhosis.

Methods: We developed a microsimulation model of the natural history of HCC in individuals with compensated cirrhosis. We compared the cost-effectiveness of biannual surveillance using 2 blood-based biomarkers-HES V2.0 and GALAD-versus ultrasound-based surveillance across a range of sensitivity, specificity, test costs, and adherence levels. Outcomes included quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios …

Targeting Oncogenic Flt3 Uncovers A Ferroptosis Vulnerability Through Selenocysteine Recoding In Acute Myeloid Leukaemia, Ken Furudate, Ayumi Kitano, Taotao Tan, Mengdie Feng, Jing Zhou, Tao Wang, Robert J Taylor, Alexandra M Stevens, Md Abul Hassan Samee, Jeffrey A Magee, Koichi Takahashi, Daisuke Nakada

Faculty, Staff and Students Publications

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the …

Glioblastoma Stem Cell Growth Requires Dot1l-Med23 Control Of Enhancer Accessibility, Amy Banks, Graham Macleod, Ravinder K Bahia, Emilie Cutts, Michael J Johnston, Orsolya Cseh, Stephane Angers, Ana Nikolic, Marco Gallo, H Artee Luchman, Samuel Weiss

Faculty, Staff and Students Publications

Harboring a low mutational burden, glioblastoma relies on various epigenetic regulators to fuel its development and progression, several of which remain mechanistically enigmatic. Here, we show that the histone methyltransferase DOT1L shapes chromatin accessibility of glioblastoma stem cell enhancer elements to reversibly regulate fate- and growth-related transcriptional programs. A genome-wide chemogenomic knockout screen reveals that the mediator complex tail module subunit, MED23, is essential for glioblastoma stem cell growth arrest following DOT1L inhibition, critically relying on CCND2 repression. MED23 knockout (KO) glioblastoma stem cells do not display the chromatin accessibility changes at enhancer elements following DOT1L inhibition. Consequently, MED23-KO rescues …

Oncogenic Pik3ca Reprograms Glutamine Metabolism To Drive Bladder Cancer Progression, Jun Hyoung Park, Aaditya Krishna Arun, Sachin B Jorvekar, Yongchao Dou, Mohammed Khurshidul Hassan, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Jun Xu, Daniel Kraushaar, Adriana Langer Gramer, Allison C Bellman, Leomar Y Ballester, Yuan Xu, Robert Taylor Ripley, Seth P Lerner, Roni J Bollag, Martha K Terris, Chong-Xian Pan, Benny Abraham Kaipparettu, Yair Lotan, Nagireddy Putluri

Faculty, Staff and Students Publications

Background: Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined.

Methods: To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study …

Using Mohs Micrographic Surgery To Treat A Large, Pedunculated Trichoblastoma On The Upper Cutaneous Lip, Richard G. Bindernagel Jr., Addie Walker, Richard Miller

HCA Healthcare Journal of Medicine

Trichoblastomas are uncommon adnexal tumors that usually occur on the face. We report a case of a 62-year-old White man with a large, asymptomatic, slow-growing lesion that had been on his right upper cutaneous lip for 15 years. A 2 cm pink, pedunculated nodule with telangiectasia was seen on examination. A shave biopsy was consistent with trichoblastoma: a circumscribed-appearing dermal tumor of basaloid cells arranged in cords and islands within a cellular stroma, focal epidermal connection, and papillary mesenchymal bodies. The patient elected for treatment with Mohs micrographic surgery (MMS) given the length of time that the tumor had been …

Chemotherapeutic Induction Of Cytosolic Single-Stranded Dna Accumulation Sensitizes Triple-Negative Breast Cancer To Immunotherapy, Jianli Zhou, Zhicheng Zhou, Ruoxi Yuan, Rui Ye, Anh Thai Quynh Nguyen, Kishor Bhatia, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Background: Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.

Methods: Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, …

Folr1-Targeted Actinium-225-Based Alpha-Particle Therapy Eliminates Ovarian Cancer, Neetu Singh, Esther Need, Ayden Berndt, Matthew Goff, Lydia J. Wilson, Firas Mourtada, Feng Guo, Tara Mastren, Taslim Al-Hilal, Anil K. Sood, Amit Maity, Scott C. Miller, Satoshi Minoshima, Shreya Goel, Sixiang Shi

Department of Radiation Oncology Faculty Papers

Despite the advancement in therapies, ovarian cancer treatment is challenging because of poor prognosis and high relapse associated with acquired resistance. Emerging targeted alpha particles, particularly actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. Here, we describe a successful example of folate receptor 1 (FOLR1)–targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal positron emission tomography imaging demonstrated high tumor-specific uptake of αFOLR1 (anti-FOLR1 antibody) in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy, achieving marked tumor regression, 80% survival, and 40% complete tumor elimination. The therapy resulted in tumor-specific double-stranded DNA damage, and …

In Vivo Orf Overexpression Screening Identifies Ccn4 As A Regulator Of Glioblastoma Growth Validated Across Multiple Models

Faculty, Staff and Students Publications

Despite current multimodal therapies for glioblastoma (GBM), its prognosis remains grim. Thus, a tremendous need exists to identify new genetic drivers that may serve as potential therapeutic targets in glioblastoma (GBM). We describe an in vivo overexpression screening strategy to identify drivers of glioblastoma where we have leveraged TCGA datasets to conduct a functional genomics screen of prioritized open reading frames (ORFs) that are overexpressed and/or amplified in GBM. To interrogate these potential drivers within a more relevant physiological context, the screening was accomplished in vivo in an orthotopic patient-derived glioma stem-like cell (GSC) model. Among 5 positive "hits" from …

Notch1 Acts As A Tumor Suppressor That Induces Early Differentiation In Head And Neck Cancer, Kazi M Ahmed, Kalil Saab, Defeng Deng, Jiping Wang, Xiayu Rao, Jiexin Zhang, Yuanxin Xi, Jing Wang, Zhiyi Liu, Noriaki Tanaka, David A Wheeler, Eve Shinbrot, Rami Saade, Curtis R Pickering, Tong-Xin Xie, Adel K El-Naggar, Abdullah A Osman, Kunal Rai, Patrick A Zweidler-Mckay, John V Heymach, Lauren A Byers, Faye M Johnson, Vlad C Sandulache, Jeffrey N Myers, Pedram Yadollahi, Mitchell J Frederick

Faculty, Staff and Students Publications

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early …

Histone Deacetylase Enzyme Activity Is Not The Universal Anticancer Target Of Hdac Inhibitors, Wenbo Li, Hyun-Hwan Jeong, Chengchuang Song, Panpan Liu, Yingjie Chang, Hao Fang, Udhaya Kumar S, Yuxiang Sun, M James You, Dongyin Guan, Zhandong Liu, Leng Han, Xuben Hou, Zheng Sun

Faculty, Staff and Students Publications

Histone deacetylase inhibitors (HDIs) are approved for treating hematologic cancers and are currently being evaluated in hundreds of clinical trials for various cancers and other diseases, although their mechanisms of action remain poorly understood. Here, our unbiased bioinformatics analyses found that, for most cancer types, expression levels or genetic variants of histone deacetylase (HDACs) do not consistently correlate with carcinogenesis, do not predict cancer patient survival, and do not associate with cellular responses to HDIs. Whole-genome CRISPR library screens did not identify HDACs as genes affecting cellular responses to HDIs. Overexpression of dominant-negative Class I HDACs causes similar protein hyperacetylation …

Integrated Proteogenomic And Metabolomic Profiling Of Acute Myeloid Leukemias To Identify Molecular Subtypes And Associated Therapy Targets, Jennifer E Kyle, Raghav Jain, Yamei Deng, Marina A Gritsenko, Leanne E Henry, Jonathan T Lei, Yongchao Dou, Bahar Tercan, Zhiao Shi, Mahnoor N Gondal, Chia-Feng Tsai, John M Elizarraras, Rosalie K Chu, Fengchao Yu, Sunil K Joshi, Xiaojun Jing, Daniel A Polasky, Karl K Weitz, Ginny Xiaohe Li, Vanessa L Paurus, Chaevien S Clendinen, Athena A Schepmoes, Priscila M Lalli, Josie G Eder, Javier E Flores, Kelly G Stratton, James C Pino, Camilo Posso, Vladislav A Petyuk, Tyler J Sagendorf, Yuanwei Xu, Omar M Ibrahim, Ronald J Moore, Rui Zhao, Jin Chen, Matthew E Monroe, Mathangi Thiagarajan, Galen Hostetter, Chelsea Newton, Eunkyung An, Ana I Robles, Xu Zhang, Nathan J Edwards, Yin Lu, Hui Zhang, Haitham Abdelhakim, Paul D Piehowski, Mehdi Mesri, Richard D Smith, Chandan Kumar-Sinha, Cristina E Tognon, Jennifer Dunlap, Elie Traer, Li Ding, Jeffrey W Tyner, Arul M Chinnaiyan, Gilbert S Omenn, Karin D Rodland, Saravana M Dhanasekaran, Sara J C Gosline, Alexey I Nesvizhiskii, Bing Zhang, Tao Liu, Marcin P Cieslik, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematological malignancy. Here, to better define this clinically taxing and translationally challenging malignancy, we applied a multiomics approach, consisting of 13 modalities to analyze 173 treatment-naive individuals with AML. By integrating these 'omes', we identified distinct AML subtypes, genotype-phenotype associations, biomarkers and pathobiological mechanisms. Across the spectrum of primitive and committed AML, we found extensive metabolomic and lipidomic reprogramming driven by divergent MYC and mTOR activity. We linked metabolic changes to striking hyperacetylation of mitochondrial proteins in CEBPA-mutant AML. Protein-centric subtyping revealed a distinct NPM1-mutant subset characterized by outlier expression …

Tak1 Is A Key Regulator Of Oncogenic Signaling And Differentiation Blockade In Rhabdomyosarcoma, Kavya Mathukumalli, Phuong T Ho, Raksha Bhat, Meiricris Tomaz Da Silva, Tagari Samanta, Meghana V Trivedi, Bin Guo, Benny A Kaipparettu, Ashok Kumar

Faculty, Staff and Students Publications

Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma with a skeletal muscle phenotype, accounting for approximately 50% of all pediatric soft tissue sarcomas and 8% of all childhood cancers. Although RMS cells express myogenic regulatory factors, they fail to undergo terminal differentiation into mature muscle cells. Transforming growth factor β-activated kinase 1 (TAK1) is a key signaling mediator that activates multiple intracellular pathways, yet its role in RMS has remained unknown. Here, we show that TAK1 expression and activity are markedly elevated in RMS cell lines and patient tumor specimens. RNA-Seq and reverse phase protein array (RPPA) analyses revealed that …

Chemotherapy-Induced Activation Of Caspase-1 And Il-1Α Release By Cancer Cells Remotely Skews Myelopoiesis To Drive Pro Tumorigenic Systemic Neutrophil-Dominant Inflammation, Yung Hsing Huang, Hongbo Gao, Haley E Garcia, Sophie J Porter, Mustafa Karabicici, Xen Ping Hoi, Mark D Alonzo, Armine Kasabyan, Efrosini Tsouko, Crystal S Shin, Lisa Bouchier-Hayes, Dimitrios Korentzelos, Chen Chen, Michael Brooks, Zheng Yin, Renil S Titus, Lan Zhou, Yinan Gong, Yulin Li, Stephen Tc Wong, Ziad El-Zaatari, Dharam Kaushik, Raj Satkunasivam, Fotis Nikolos, Keith S Chan

Faculty, Staff and Students Publications

While chemotherapy-induced tumor cell death is known to modulate the local immune landscape, its systemic impact on distant bone marrow—a site essential for immune cell maturation—remains underexplored. Here, we show that gemcitabine chemotherapy induces inflammatory caspase-1-dependent pyroptosis in epithelial cancer cells (epiCaspase-1). Despite its inflammatory nature, epiCaspase-1-mediated cell death is non-immunogenic. Clinically, elevated expression of an epiCaspase-1 gene signature correlates with worse patient outcomes. Mechanistically, epiCaspase-1 triggers the noncanonical release of IL-1α through NINJ1 lytic pores, remotely skewing bone marrow hematopoiesis towards granulocyte-monocyte progenitors and mature neutrophil output. This systemic reprogramming elevates the neutrophil-to-lymphocyte ratio (NLR) in both peripheral blood …

A Unique Case Of Tumor Thrombus In The Superior Vena Cava (Svc), John Leece, Juan Rodriguez

Central & West Texas and San Antonio GME Research Day 2026

No abstract provided.

Loss Of Znrf3/Rnf43 Unleashes Egrfr In Cancer, Megan N Michalski, Weiyu Jiang, Jianghua Tu, Zhongcheng Shi, Yongchao Dou, Yi Wang, Xin-Hua Feng, Galen Hostetter, Xiangwei Wu, Shixia Huang, Noah F Shroyer, Bing Zhang, Bart O Williams, Qingyun Liu, Xia Lin, Yi Li

Faculty, Staff and Students Publications

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of …

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Arghadip Dey, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

Co-Occurrence Of Transcriptionally Distinct Persister Cell States Underpins Neoadjuvant Therapy Resistance In Triple-Negative Breast Cancer, Nora J Doleschall, Kate Moore, Gareth Muirhead, Ram Rajaram Srinivasan, Ping Gong, Jonathan T Lei, Amy Fleming, Hwei Minn Khoo, Naomi Guppy, Gabrielle Elshtein, Mohammed Inayatullah, Vijay K Tiwari, Lacey E Dobrolecki, Michael T Lewis, Syed Haider, Rachael Natrajan

Faculty, Staff and Students Publications

Background

Although the addition of neoadjuvant immune checkpoint blockade to chemotherapy has improved patient outcome in early triple‑negative breast cancer (TNBC), some patients continue to have poor disease outcomes.

Methods

To characterise neoadjuvant chemotherapy (NAC) resistant cell populations that persist post-NAC, we created a high-resolution single-cell atlas of 129,433 cells from fourteen TNBC patient-derived xenograft (PDX) models with residual disease post-NAC. We identified transcriptionally distinct cancer subpopulations or cell states using unsupervised clustering and characterised‑ their regulatory network as well as clinical associations with treatment response, metastatic progression and survival. Findings were validated using multiple independent TNBC cohorts.

Results

Four …

Regulation Of Mitochondrial Ros By C15orf48 In A Basal Cell Subpopulation Contributes To Chemotherapy Resistance In Tnbc, Yuan Qi, Steven W Wall, Xiaomei Zhang, Jiansu Shao, Sabrina Jeter-Jones, Shirong Cai, Faiza Baameur Hancock, Gloria V Echeverria, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Students Publications

Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 …

The Integrated 31-Gene Expression Profile Test Identifies Low-Risk Patients With Cutaneous Melanoma Who Can Forego The Slnb Procedure: Results From A Prospective, Multicenter Trial., Timothy Beard, J Michael Guenther, Stanley P Leong, Maki Yamamoto, Samuel Dierks, Brenda Sickle-Santanello, Andrew Ward, Mark Cripe, Parth Shah, Shawn Young

Oncology Articles

AIMS: Prospectively confirm use of the integrated 31-gene expression profile test (i31-SLNB) in patients with cutaneous melanoma to predict sentinel lymph node biopsy (SLNB) positivity and assess recurrence rates in those considered low risk by i31-SLNB who did not have an SLNB.

METHODS: Patients with T1-T4 tumors being considered for SLNB who received 31-gene expression profile (31-GEP) testing in the multi-center, prospective DECIDE study were included (n = 912). Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS).

RESULTS: Among 430 patients with T1-T4 tumors who had an SLNB, the positivity rate was 2.6% (3/114) in those with < 5% i31-SLNB-predicted risk versus 21.4% (28/131) in those with >10% predicted …

Gompertz Growth With A Shared Carrying Capacity Optimally Simulates Primary And Metastatic Tumor Growth Dynamics, Pirmin Schlicke, Preethi Korangath, Xiaoxi Pan, Caner Ercan, Kathleen Gabrielson, Yinyin Yuan, Robert Ivkov, Heiko Enderling

Faculty, Staff and Student Publications

Background: Cancer is a systemic disease with most deaths attributed to metastatic burden. Primary and metastatic tumors, albeit at different anatomic locations, are interconnected through multiple biological processes. Pre-clinical and clinical observations of growth acceleration of metastases after surgery, or abscopal effects outside the radiation field are widely reported, yet reliably triggering favorable and avoiding unfavorable systemic responses remains an unmet clinical need. Understanding local and systemic tumor interaction dynamics will help guide future treatments.

Methods: We analyze the data of multiple in vivo tumor models. We formalize the systemic interplay of tumors as mathematical differential equation and calibrate parameters …

Unraveling The Nexus: Tumor Mutational Burden, Pd-L1 Expression, And Oncogenic Alterations In Non-Small Cell Lung Cancer Cytology Specimens, Min Dai, Francis Anthony San Lucas, Hector Alvarez, Leomar Ballester, Hui Chen, Asif Rashid, Mark J Routbort, Gloria Sura, Keith Sweeney, Gokce Toruner, Peng Wei, Richard Yang, Hyvan Dang, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri

Faculty, Staff and Student Publications

Background: PD-L1 expression and tumor mutational burden (TMB) are biomarkers for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC); however, patients harboring oncogenic alterations have limited benefit from ICIs. The impact of oncogenic alterations on TMB and PD-L1 tumor proportion score in lung cytology specimens is poorly understood. Herein, the association between oncogenic alterations, TMB, and PD-L1 in NSCLC cytology specimens is explored.

Methods: Next-generation sequencing results from 312 NSCLC cytology specimens were retrospectively reviewed that interrogate 610 genes and select immuno-oncology signatures. TMB and PD-L1 immunohistochemical expression across oncogenic alterations were analyzed to explore associations.

Results: …

Multiparametric Mri To Predict Response To Irreversible Electroporation Plus Anti-Pd-1 Immunotherapy In Pancreatic Ductal Adenocarcinoma, Qizhen Cao, Mark D Pagel, Charles V Kingsley, Jingfei Ma, James P Long, Seth T Gammon, Sanaz Javadi, Chun Li

Faculty, Staff and Student Publications

Purpose: To investigate contrast-enhanced T1-weighted MRI and diffusion-weighted magnetic resonance imaging (DWI) for early prediction of tumor response to combined irreversible electroporation (IRE) and anti-PD-1 immunotherapy.

Methods: Murine pancreatic ductal adenocarcinoma (PDAC) cells KRAS* were inoculated into the pancreas of C57BL/6 mice. IRE was performed when tumors became palpable. After IRE, mice received six intraperitoneal injections of anti-PD-1 over 2 weeks. T2-weighted MRI, T1-weighted MRI with macromolecular contrast agent poly(L-glutamic acid)-conjugated gadolinium (PG-Gd), and DWI were performed before and after IRE. Survival was analyzed using Kaplan-Meier curves. Mice surviving at least 100 days without recurrence after IRE were considered complete …

Breast Cancer-Derived Extracellular Vesicle Mir-425-5p (Mir-425) Promotes Brain Metastasis Via Activating Astrocytes Through The Novel Mir-425-Znf24-Ccl8 Signaling Axis, Ravi Singh

Faculty, Staff and Student Publications

Mechanisms underlying breast cancer brain metastasis (BCBM) are still not well understood. Here, we identified that BCBM patient serum contained extracellular vesicles (EVs) with high levels of microRNAs (miRNAs)-107 and -425. Levels of miR-107 and miR-425 were elevated in brain metastases, and the elevation was associated with poor patient prognoses. Ectopic expression of miR-107 and miR-425 promoted mammospheres; however, the inhibition of miR-425, but not miR-107, suppressed breast cancer mammosphere formation. We further observed that EVs from miR-425-overexpressing breast cancer cells strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-425-activated astrocytes promoted mammospheres. To elucidate how …

The Hexosamine Biosynthetic Pathway Alters The Cytoskeleton To Modulate Cell Proliferation And Migration In Aggressive Prostate Cancer, Michael Y Young, Emily Cousino, Christine B Magdongon, Raju Gajjela, Basil B Mattamana, Alexander Zaslavsky, Ganesh S Palapattu, Arun Sreekumar, Dileep Varma

Faculty, Staff and Students Publications

Castration-resistant prostate cancer (CRPC) progresses despite androgen deprivation therapy, as cancer cells adapt to grow without testosterone, becoming more aggressive and prone to metastasis. CRPC biology complicates the development of effective therapies, posing challenges for patient care. Recent gene-expression and metabolomics studies highlight the Hexosamine Biosynthetic Pathway (HBP) as a critical player, with key components like GNPNAT1 (Glucosamine-phosphate N-acetyltransferase 1) being downregulated in CRPC. GNPNAT1 knockdown in pre-clinical models has been shown to increase growth and metastasis in CRPC tumors, though the mechanisms remain unclear.To investigate the cellular basis of these CRPC phenotypes, we generated a CRISPR-Cas9 knockout model of …