Biomedical Informatics Commons^™

An Isoform-Specific Runx1c-Btg2 Axis Governs Aml Quiescence And Chemoresistance, Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl Mckenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang

Faculty, Staff and Student Publications

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. …

Targeting Aldh16a1 Mediated Thioredoxin Lysosomal Degradation To Enhance Ferroptosis Susceptibility In Smarca4-Deficient Nsclc, Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang, Boyi Gan, Cheng Zhan

Faculty, Staff and Student Publications

Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN's oxidoreductase function by occluding its active site. We also show that …

Inhibition Of Mcl-1 And Mek Overcomes Mek Inhibitor Resistance In Triple-Negative And Inflammatory Breast Cancers, Mohd Mughees, Moises Tacam, Alex W Tan, Mary Kathryn Pitner, Lakesla R Iles, Xiaoding Hu, Emilly S Villodre, Bisrat G Debeb, Takahiro Kogawa, Bora Lim, Rachel M Layman, Wendy A Woodward, Naoto T Ueno, Debu Tripathy, Savitri Krishnamurthy, Yuan Qi, Lajos Pusztai, Jian Wang, Varsha Gandhi, Geoffrey Bartholomeusz, Chandra Bartholomeusz

Faculty, Staff and Student Publications

The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that the MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and …

Efficacy Of Atr Kinase Inhibitor Elimusertib Monotherapy Or Combination In Tumors With Dna Damage Response Pathway And Other Genomic Alterations, Kaushik Varadarajan, Christian X Cruz Pico, Kurt W Evans, Maria Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dhruv Chachad, Timothy P Diperi, Bailiang Wang, Stephen M Scott, Ming Zhao, Argun Akcakanat, Antje M Wengner, Timothy A Yap, Funda Meric-Bernstam

Faculty, Staff and Student Publications

The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia-mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY-1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR), ≥30% decrease in TV; ≥20% increase in TV, progressive disease; and non-PR/progressive disease, stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. …

Mucinous Cystic Neoplasms Of The Pancreas And Liver Share A Similar Dna Methylation Profile With Mucinous Ovarian Tumors, Zoe Leoni, Teodor G Calina, Tobias Janik, Elena Grafenhorst, Eliane T Taube, Christopher Cm Neumann, Baoqing Chen, Elena I Braicu, Jalid Sehouli, Thomas Malinka, Wenzel Schöning, Johann Pratschke, George A Calin, David S Klimstra, Jamal K Benhamida, Irene Esposito, Markus Möbs, David Horst, Simon Schallenberg, David Capper, Mihnea P Dragomir

Faculty, Staff and Student Publications

The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 …

Trop2 Expression In Salivary Gland Adenoidcystic Carcinoma (Acc) According To Histologic Subtype: Therapeutic Implications, Juliana Mota Siqueira, Yoshitsugu Mitani, Mario L Marques-Piubelli, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mutsumi Mitani, Giovanna Lopes Carvalho, Fabio Daumas Nunes, Leandro Luongo Matos, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

Background: Adenoid cystic carcinoma (ACC) is a common salivary gland carcinoma with high recurrence and distant metastasis rates. Currently, there is no standard systemic treatment available. TROP2 is a transmembrane glycoprotein involved in the oncogenesis of several tumors that can be therapeutically targeted by a TROP2-antibody-drug conjugate (ADC). We aimed to characterize TROP2 expression in ACC and assess TROP2 as a potential therapeutic target.

Methods: TROP2 immunohistochemistry was performed in a tissue microarray including 165 ACC of salivary gland. The tumors were grouped according to the histological pattern as non-solid, solid + non-solid, or solid. TROP2 protein expression in ACC …

Secretogranin 2 Binds Lilrb4 Resulting In Immunosuppression, Xing Yang, Ryan Huang, Meng Fang, Yubo He, Jingjing Xie, Xiaoye Liu, Chengcheng Zhang, Qi Lou, Mi Deng, Wei Xiong, Cheryl Lewis, Zade Sadek, Ankit Gupta, Lianqi Chen, Xuewu Zhang, Lei Guo, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are important in a variety of physiological and pathological contexts, including tumor development, but how hormones might regulate their activity is unclear. Secretogranins, a family of secretory proteins in endocrine and neuronal cells, are proposed to function as prohormones or hormones, but their specific receptors are unknown. Here we show that secretogranin 2 (SCG2), a granin family member, functionally interacts with leukocyte immunoglobulin-like receptor B4 (LILRB4) on monocytic cells. Tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner, whereas SCG2 deficiency in host mice impairs tumor progression and reduces infiltration of …

Using Extension-Based Mrna Display To Design Antibody-Like Proteinogenic Peptides For Human Pd-L1, Justin N Ong, Brian J Grindel, Scott A Rankin, Sarah H Naylon, Anupallavi Srinivasamani, Guillaume J Trusz, Xiaowen Liang, Md Nasir Uddin, Lauren Fuller, Michael Curran, Stephane P Roche, Terry T Takahashi, Richard W Roberts, Steven W Millward

Faculty, Staff and Student Publications

Many peptide drugs rely on nonproteinogenic amino acids and chemical modifications for improved activity and proteolytic stability. However, these features also make drug production expensive and challenging to scale. Here, we engineered small, linear, proteinogenic peptides that bind human programmed death-ligand 1 (hPD-L1) with high affinity and stability using mRNA display affinity maturation. The resulting peptides, SPAM2 and SPAM3, have antibody-like affinities for hPD-L1 (dissociation constants between ~250 and 300 pM) and are selective for hPD-L1. Both SPAM2 and SPAM3 compete with hPD-L1 ligands known to interact with the programmed cell death protein 1 site and are stable in human …

Spatial Colocalization And Molecular Crosstalk Of Myofibroblastic Cafs And Tumor Cells Shape Lymph Node Metastasis In Oral Squamous Cell Carcinoma, Ken Furudate, Shuya Kasai, Tadashi Yoshizawa, Yuya Sasaki, Kohei Fujikura, Shintaro Goto, Ryohei Ito, Koki Takagi, Tomoyuki Tanaka, Hiroshi Kijima, Kosei Kubota, Ken Itoh, Wataru Kobayashi, Koichi Takahashi

Faculty, Staff and Student Publications

Lymph node metastasis (LNM) is a critical prognostic factor for patients with oral squamous cell carcinoma (OSCC). Previous research has implicated the partial epithelial-to-mesenchymal transition of tumor cells and myofibroblastic cancer-associated fibroblasts (myCAFs) in the LNM process. However, the underlying molecular mechanisms remain poorly understood. Here, we conducted a comprehensive molecular analysis integrating original and publicly available OSCC data from bulk genome and transcriptome, single-cell transcriptome, and spatial transcriptome analyses. We found that myCAFs were quantitatively and functionally activated in LNM-positive samples and spatially colocalized with OSCC cells within the invasive tumor front (ITF), providing a niche that may facilitate …

In Situ Programming Of The Tumor Microenvironment To Alleviate Immunosuppression For Pancreatic Cancer Immunotherapy, Man Sun, Huan Zhang, Yarui Ma, Simiao Wang, Jiayi Chen, Yaxin Cui, Yun Zhang, Siyuan Hu, Dan Zhou, Pengchen Zhang, Yahui Liu, Betty Y S Kim, Wen Jiang, Xiaobing Wang, Zhaogang Yang

Faculty, Staff and Student Publications

Recent studies have highlighted the pivotal role of the cGAS‐STING pathway in cancer immunotherapy. However, clinical trials with cGAS‐STING pathway agonists have faced setbacks thanks to their short biological half‐life, lack of tumor specificity, and potential to promote tumor immune evasion. To address these challenges, a novel exosome‐based drug delivery platform, termed cmExoaCD11b is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExoaCD11b is engineered to encapsulate high copy numbers of IL‐12 mRNA and 2′3’‐cGAMP (cGAMP) and is functionalized with CD11b antibodies for targeted delivery to macrophages. Notably, cmExoaCD11b facilitated the …

Expression Graph Network Framework For Biomarker Discovery, Yang Liu, Jason Huse, Kasthuri Kannan

Faculty, Staff and Student Publications

Biomarker discovery for complex diseases, such as cancer, hinges on uncovering molecular signatures that capture intricate, interconnected relationships within biological data-a challenge that traditional statistical and machine learning methods often fail to meet due to the complexity of high-dimensional gene expression profiles. To overcome this, we introduce the expression graph network framework (EGNF). This cutting-edge graph-based approach integrates graph neural networks with network-based feature engineering to enhance the predictive identification of biomarkers. EGNF constructs biologically informed networks by combining gene expression data and clinical attributes within a graph database, utilizing hierarchical clustering to generate dynamic, patient-specific representations of molecular interactions. …

Adams Contribute To Triple Negative Breast Cancer Via Mtorc1 Pathway: Targeting Adam-Mtor Axis Improves Efficacy, Shuying Liu, Huiqin Chen, Mihai Gagea, Lorenzo Federico, Fan Zhang, Javier Gomez, Kim-Anh Do, William F Symmans, Gabriel N Hortobagyi, Gordon B Mills, Ana M Gonzalez-Angulo, Debasish Tripathy

Faculty, Staff and Student Publications

Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, …

Nf1-Depleted Er+ Breast Cancers Are Differentially Sensitive To Cdk4/6 Inhibitors, Ze-Yi Zheng, Anran Chen, Eric J Jaehnig, Meenakshi Anurag, Jonathan T Lei, Long Feng, Chenwei Wang, Diana Fandino, Purba Singh, Hilda Kennedy, Ghazal Yadav, Craig T Vollert, Jill Tsai, Xi Chen, Yi Li, Bora Lim, Alastair Thompson, Shunqiang Li, Charles E Foulds, Bing Zhang, Matthew J Ellis, Eric C Chang

Faculty, Staff and Students Publications

Neurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase activating protein and estrogen receptor (ER) transcriptional corepressor. NF1low status, identified by copy number loss or low mRNA/protein expression is associated with endocrine therapy resistance in approximately 20% of ER+/HER2− (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1low ER+/HER2− breast cancer is therefore a priority. In this study proteogenomic analysis of ER+/HER2− breast cancer demonstrated that NF1low tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, NF1-deletion had a dual effect on CDK4 activity. First, by promoting ER recruitment to CCND1 …

Prolonging Lung Cancer Response To Egfr Inhibition By Targeting The Selective Advantage Of Resistant Cells, Lisa Brunet, David Alexandre, Jiyoung Lee, Maria Del Mar Blanquer-Rosselló, David Bracquemond, Alexis Guernet, Houssein Chhouri, Mathilde Goupil, Zoulika Kherrouche, Arnaud Arabo, Maicol Mancini, Dorthe Cartier, Shen Yao, David Godefroy, Julie Dehedin, Jian-Rong Li, Céline Duparc, Philippe Jamme, Audrey Vinchent, Caroline Bérard, David Tulasne, Sabrina Arena, Alberto Bardelli, Chao Cheng, Byoung Chul Cho, Olivier Wurtz, Cédric Coulouarn, Antonio Maraver, Stuart A Aaronson, Alexis B Cortot, Youssef Anouar, Luca Grumolato

Faculty, Staff and Students Publications

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Through a DNA barcoding approach, we show that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK-interacting kinase (MKNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and …

Circzfr/Ythdf3 Axis Drives Lymph Node Metastasis In Cervical Cancer Via Fasn Translation, Mingyi Zhou, Yan Gao, Yong Zhang, Lian He, Bo Gao, Yue Zhang, Francois X Claret, George A Calin, Danbo Wang

Faculty, Staff and Student Publications

Background: Lymph node metastasis is a key driver of poor outcomes in cervical cancer. However, the molecular mechanisms of circular RNAs (circRNAs) driving cervical cancer lymph node metastasis remain unclear.

Methods: We identified circZFR, fatty acid synthase (FASN) and YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) protein expression in the cervical cancer patients with long and short disease-free survival (DFS). Functional experiments were performed to investigate the function of circZFR, FASN and YTHDF3 on cell migration and invasion. MeRIP-qPCR, RNA pulldown, RNA Immunoprecipitation (RIP), and Co-Immunoprecipitation (Co-IP) assays were executed to investigate the mechanism of circZFR regulating FASN protein expression. …

Therapeutic Targeting Of Syndecan-1 Axis Overcomes Acquired Resistance To Kras-Targeted Therapy In Gastrointestinal Cancers, Madelaine S Theardy, Mitsunobu Takeda, Alexey Sorokin, Shuaitong Chen, Zecheng Yang, Xiaofei Wang, Preeti Kanikarla, Oluwadara Coker, Phuoc Nguyen, Yongkun Wei, Jun Yao, Liang Yan, Yanqing Jin, Yiming Cai, Masakatsu Paku, Ziheng Chen, Kara Z Li, Francesca Citron, Hideo Tomihara, Sisi Gao, Angela K Deem, Jun Zhao, Huamin Wang, Samir Hanash, Ronald A Depinho, Anirban Maitra, Giulio F Draetta, Haoqiang Ying, Scott Kopetz, Wantong Yao

Faculty, Staff and Student Publications

The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated …

Multidimensional Analysis Of B7 Homolog 3 Rna Expression In Small Cell Lung Cancer Molecular Subtypes, Carl M Gay, Taofeek K Owonikoko, Lauren A Byers, Noura J Choudhury, Sajid Ahmed, Zachary Cain, Xiaozhong Qian, Matthew Brentnall, Simon Heeke, Ming Poi, Sharon Wu, Charles M Rudin

Faculty, Staff and Student Publications

Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.

Experimental design: Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor …

Keap1 And Stk11/Lkb1 Alterations Enhance Vulnerability To Atr Inhibition In Kras Mutant Non-Small Cell Lung Cancer, Ana Galan-Cobo, Natalie I Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro G Paula, Marlese Pisegna, Daniel J Mcgrail, Alissa Poteete, Sungnam Cho, Minh Truong Do, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc'h, Adina Hughes, Rebecca Sargeant, Lucy Young, Li Shen, Gozde Kar, Caezaan Keshvani, Claudio Arrechedera, Sharia Hernandez, Katharina Schlacher, Jing Wang, Sonia Iyer, James Conway, Mohamed Reda Keddar, Marta Milo, Ilario De Toma, Susan E Critchlow, J Carl Barrett, Jan Cosaert, Alan Lau, Viia Valge-Archer, Lauren A Byers, Simon T Barry, John V Heymach

Faculty, Staff and Student Publications

KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of KEAP1 alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype …

Mutant P53 Confers Chemoresistance By Activating Kmt5b-Mediated Dna Repair Pathway In Nasopharyngeal Carcinoma, Haidan Luo, Mo-Fan Huang, An Xu, Donghui Wang, Julian A Gingold, Jian Tu, Ruoyu Wang, Zijun Huo, Yen-Ting Chiang, Kuang-Lei Tsai, Jie Su, Danielle A Bazer, Mien-Chie Hung, Canmao Xie, Yubiao Guo, Dung-Fang Lee, Huiling Yang, Ruiying Zhao

Faculty, Staff and Student Publications

Nasopharyngeal carcinoma (NPC), a malignancy arising from the nasopharyngeal epithelium, is common in the east and southeast area of Asia. Treatments for locally advanced and recurrent NPC include chemotherapy (usually combined with 5-Fluorouracil, 5-FU) and radiotherapy, but response is limited due to chemo-resistance. p53 mutation is a critical factor for 5-FU resistance in some cancers, but its role in NPC chemo-resistance remains unclear. Here, we demonstrate that p53(R280T), a common p53 somatic mutation found in multiple NPC tumor samples, induces gain-of-function upregulation of DNA repair genes which leads to 5-FU resistance in NPC. p53(R280T) specifically upregulates the expression of DNA …

Integrating Ctdna Analysis And Radiomics For Dynamic Risk Assessment In Localized Lung Cancer, Everett J Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B Hui, Barzin Y Nabet, Yufei Liu, Jacob J Chabon, Michael S Binkley, David M Kurtz, Emily G Hamilton, Aadel A Chaudhuri, Chih Long Liu, Zhe Li, Rene F Bonilla, Alice L Jiang, Brianna C Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J Ramchandran, Sukhmani K Padda, Joel W Neal, Heather A Wakelee, Michael F Gensheimer, Billy W Loo, Ruijiang Li, Steven H Lin, Ash A Alizadeh, Maximilian Diehn

Faculty, Staff and Student Publications

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. Circulating tumor DNA (ctDNA) minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. Here, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration …

Rna Sequencing And Immunohistochemistry Jointly Improve Tumor Biomarker Interpretation, Vladimir Kushnarev, Danil Stupichev, Suren Davitavyan, Kirill Kriukov, Basavaraja U Shanthappa, Anna Butusova, Sofia Menshikova, Anna Belozerova, Anastasia Shvyrkova, Arina Tkachuk, Olga Khatenkova, Linda Balabanian, Ekaterina Postovalova, Jochen K Lennerz, Funda Meric-Bernstam, Alexander Bagaev

Faculty, Staff and Student Publications

This study aimed to assess the correlation between RNA sequencing (RNA-seq) and immunohistochemistry (IHC) in detecting key cancer biomarkers across solid tumors, and then, to establish RNA-seq thresholds that accurately reflect clinical IHC classifications. Expression levels of nine biomarkers-ESR1, PGR, AR, MKI67, ERBB2, CD274, CDX2, KRT7, and KRT20-were analyzed in 365 formalin-fixed, paraffin-embedded samples from breast, lung, gastrointestinal, and other solid carcinomas. Correlations between RNA-seq data and IHC scores were determined using Spearman's correlation coefficients, with RNA-seq cut-offs established to distinguish positive from negative IHC scores. The results revealed strong correlations for most biomarkers, with coefficients ranging from 0.53 to …

Gd3 Synthase Drives Resistance To P53-Induced Apoptosis In Breast Cancer By Modulating Mitochondrial Function, Vivek Anand, Fouad El-Dana, Natalia Baran, Jenny Borgman, Zheng Yin, Hong Zhao, Stephen T Wong, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

TP53 mutations are common in breast cancer (BC) and are associated with poor prognosis. GD3 synthase (GD3S/ST8SIA1), a gene associated with breast cancer stem cells, is upregulated in tumors with p53 mutations. However, the functional relationship between GD3S and p53 is unknown. Here, we show that GD3S levels are highest in breast tumors with specific p53 mutations. Functional studies revealed that wild-type (WT) p53 inhibits GD3S expression, whereas mutation in p53 enhances GD3S expression by upregulating GD3S promoter activity. Moreover, we found that GD3S inhibits wild-type p53-induced apoptosis in BC cells, while BC cells harboring gain-of-function p53 mutations are dependent …

Single-Cell Proteomic Analysis Reveals Multiple Myeloma Heterogeneity And The Dynamics Of The Tumor Immune Microenvironment In Precursor And Advanced States, Mohamed Kamal, Stephanie N Shishido, Jeremy Mason, Krina Patel, Elisabet E Manasanch, Robert Z Orlowski, Peter Kuhn

Faculty, Staff and Student Publications

Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone …

Characterization Of The Germline Pathogenic Mutational Landscape And Oncologic Outcomes Among 877 Patients With Invasive Lobular Carcinoma, Victoria D Huynh, Jason Mouabbi, Henry M Kuerer, Kerollos Nashat Wanis, Hiam M Abdel-Salam, Angelica M Gutierrez, Helen M Johnson, Anthony Lucci, Kelly K Hunt, Banu K Arun

Faculty, Staff and Student Publications

Purpose: There is a paucity of literature on germline pathogenic variants (gPVs) in patients with invasive lobular carcinoma (ILC). This study characterizes the landscape and compares clinicopathologic variables and treatment outcomes between those with and without gPVs.

Methods: A prospectively maintained institutional database was used to identify all patients diagnosed with nonmetastatic ILC who had germline genetic testing. Clinicopathologic characteristics and time to recurrence, contralateral cancer, and death were compared for patients with and without gPVs. Conditional hazard ratios, computed by Cox proportional hazards models, described associations between clinicopathologic factors, including gPV status, and cancer events.

Results: Of 4398 patients …

Acquired Resistance In Cancer: Towards Targeted Therapeutic Strategies, Alice Soragni, Erik S Knudsen, Thomas N O'Connor, Cristina E Tognon, Jeffrey W Tyner, Beatrice Gini, Donghwa Kim, Trever G Bivona, Xingxing Zang, Agnieszka K Witkiewicz, David W Goodrich, Dadi Jiang, Seth T Gammon, Christopher D Willey, Paul C Boutros, Vlad C Sandulache, Abdullah A Osman, Jeffrey N Myers, Kamiya Mehla, Pankaj K Singh, Keith S Chan, Hongbo Gao, Himangi Marathe

Faculty, Staff and Student Publications

Development of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics. We are at a crucial time when innovative technologies applied to patient-relevant tumour models have the potential to bridge the gap between fundamental research into mechanisms and timing of acquired resistance and clinical applications that translate these findings into actionable strategies to extend therapy efficacy. …

Melanoma Antigens In Pediatric Medulloblastoma Contribute To Tumor Heterogeneity And Species-Specificity Of Group 3 Tumors, Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Juan Sebastian Solano Gutierrez, Barbara Breznik, Anna K Lee, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer

Faculty, Staff and Student Publications

Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, …

Human Ipsc-Based Breast Cancer Model Identifies S100p-Dependent Cancer Stemness Induced By Brca1 Mutation, Jingxin Liu, Cai Zhao, Jiahao Chen, Pengguihang Zeng, Qingjian Li, Ranran Dai, Xingqiang Lai, Wenqian Song, Jianing Chen, Xixi Zhu, Xinyi Liu, Jun Sun, Jia Wang, Peihang Fang, Tengfei Wang, Wenjie Chen, Diana Guallar, Nan Cao, Jianli Zhao, Shicheng Su, Andy Peng Xiang, Yi Arial Zeng, Jie Li, Junchao Cai, Dung-Fang Lee, Jinxin Bei, Yongliang Huo, Hai Hu, Shengbao Suo, Dong-Feng Huang, Jin Bai, Junjun Ding

Faculty, Staff and Student Publications

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs). The iPSC-MCs closely resemble human primary MCs at cellular, transcriptional, and functional levels. Using this method, a breast cancer model was generated using patient-derived iPSCs harboring germline

Machine-Learning Driven Strategies For Adapting Immunotherapy In Metastatic Nsclc, Maliazurina B Saad, Qasem Al-Tashi, Lingzhi Hong, Vivek Verma, Wentao Li, Daniel Boiarsky, Shenduo Li, Milena Petranovic, Carol C Wu, Brett W Carter, Girish S Shroff, Tina Cascone, Xiuning Le, Yasir Y Elamin, Mehmet Altan, Simon Heeke, Ajay Sheshadri, Joe Y Chang, Percy P Lee, Zhongxing Liao, Don L Gibbons, Ara A Vaporciyan, J Jack Lee, Ignacio I Wistuba, Cara Haymaker, Seyedali Mirjalili, David Jaffray, Justin F Gainor, Yanyan Lou, Alessandro Di Federico, Federica Pecci, Mark Awad, Biagio Ricciuti, John V Heymach, Natalie I Vokes, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy. Benefit scores are calculated using five distinct functions derived from 28 genomic and 6 clinical features. Our integrated model, A-STEP (Attention-based …

Constitutive Il-7 Signaling Promotes Car-Nk Cell Survival In The Solid Tumor Microenvironment But Impairs Tumor Control, Matthew Dysthe, Ishwar Navin, Dayenne Van Leeuwen, Josue Pineda, Corrine Baumgartner, Cliona M Rooney, Robin Parihar

Faculty, Staff and Students Publications

Background: Adoptive transfer of chimeric antigen receptor (CAR)-expressing natural killer (NK) cells has demonstrated success against hematological malignancies. Efficacy against solid tumors has been limited by poor NK cell survival and function in the suppressive tumor microenvironment (TME). To enhance efficacy against solid tumors, stimulatory cytokines have been incorporated into CAR-NK cell therapeutic approaches. However, current cytokine strategies have limitations, including systemic toxicities, exogenous dependencies, and unwanted TME bystander effects. Here, we aimed to overcome these limitations by modifying CAR-NK cells to express a constitutively active interleukin (IL)-7 receptor, termed C7R, capable of providing intrinsic CAR-NK cell activation that does …

Detection Of Oncogenic Fusions In Colorectal Cancer Using A Partner-Agnostic Next-Generation Sequencing Approach, Andrew J Pellatt, Reagan M Barnett, Sante Gnerre, Kristin Edwards, Jason A Willis, Michael J Overmann, Kanwal Raghav, Christine M Parseghian, Arvind Dasari, M Pia Morelli, Alisha Bent, Madhulika Eluri, Nicholas Hornstein, Leylah M Drusbosky, Scott Kopetz, Van K Morris

Faculty, Staff and Student Publications

Background: Gene fusions exist with low prevalence in colorectal cancer (CRC), and the clinical utility of fusion testing in advanced CRC remains unclear. We sought to identify oncogenic fusions in patients with advanced CRC using a fusion partner-agnostic circulating tumor DNA (ctDNA) assay to better understand their clinical relevance.

Methods: We performed a retrospective analysis using de-identified data from 18,558 patients with advanced CRC who underwent ctDNA next-generation sequencing with Guardant360® from 2017 to 2022. These samples were subsequently reanalyzed with a partner-agnostic bioinformatics method to identify both clonal and non-clonal fusions. We analyzed for associations between fusions and MSI-H …