About

Michael A. Newton is a Professor in the Departments of Statistics and of Biostatistics and Medical Informatics (BMI) at the University of Wisconsin-Madison. He has been serving as chair of BMI since October 2019. Dr. Newton directs the Biostatistics and Epidemiology Research and Design (BERD) core of the Institute for Clinical and Translational Research and is a member of the Carbone Comprehensive Cancer Center, the Center for Genome Science and Innovation, and other campus research units. He currently co-chairs the Council of North American Biostatistics Chairs. Dr. Newton's research focuses on data science for basic and translational biomedicine, with contributions spanning cancer biology, immunology, genomics, methodologies for high-dimensional biostatistical inference, and theory for computational statistics. His work has been especially focused on empirical Bayesian inference calculations and has been strengthened by interdisciplinary collaborations and mentorship of talented PhD students. Dr. Newton's work has been recognized by several professional societies. He received the 2003 Mortimer Spiegelman Award from the American Public Health Association, honoring an outstanding public health statistician under age 40, and in 2004, he was named the Presidents' Award winner from the Committee of Presidents of Statistical Societies (COPSS), one of the profession's most prestigious awards. He is an elected fellow of the American Statistical Association and an elected member of the International Statistics Institute. At UW-Madison, he has been recognized as a Kellet Professor. Dr. Newton has served the scientific community in many capacities related to statistical methodology and collaborative interdisciplinary research. He also teaches various courses including clinical trials, computational statistics, Bayesian analysis, mathematical statistics, and statistical methods in molecular biology, and is a trainer in Statistics and Biomedical Data Science graduate programs.

Research topics

• Artificial Intelligence
• Data Mining
• Computer Science
• Biology
• Genetics
• Cancer research
• Internal medicine
• Immunology
• Simulation
• Oncology
• Computational biology
• Medicine

Selected publications

• Surrogate selection oversamples expanded T cell clonotypes

  The Annals of Applied Statistics · 2025-08-28

  articleOpen accessSenior author

  Surrogate selection is an experimental design that without sequencing any DNA can restrict a sample of cells to those carrying certain genomic mutations. In immunological disease studies, this design may provide a relatively easy approach to enrich a lymphocyte sample with cells relevant to the disease response because the emergence of neutral mutations associates with the proliferation history of clonal subpopulations. A statistical analysis of clonotype sizes provides a structured, quantitative perspective on this useful property of surrogate selection. Our model specification couples within-clonotype birth-death processes with an exchangeable model across clonotypes. Beyond enrichment questions about the surrogate selection design, our framework enables a study of sampling properties of elementary sample diversity statistics; it also points to new statistics that may usefully measure the burden of somatic genomic alterations associated with clonal expansion. We examine statistical properties of immunological samples governed by the coupled model specification, and we illustrate calculations in surrogate selection studies of melanoma and in single-cell genomic studies of T cell repertoires.

  PublisherOA PDFDOI

• Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the RAPGEF3/4 signaling dependency in primary melanoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-29

  articleOpen access

  ABSTRACT RAP guanine exchange factors (RAPGEF3/4) also known as EPAC1/2 (Exchange Protein Activated by cyclic AMP) are important signaling proteins. In cutaneous melanoma, we reported that loss of dependency on RAPGEF3/4 is associated with metastatic progression. Here, we investigated the molecular mechanisms underlying EPAC1/2 signaling in melanoma. Using transformed human melanocytes, chemical inhibition and genetic deletion of EPAC in Braf/Pten mice, we show that EPAC activation is an early event in melanomagenesis and is required for the growth of transformed melanocytes in vitro and melanomagenesis in vivo . Query of the Cancer Genome Atlas (TCGA) and immunohistochemical analysis of melanoma tumors showed that low EPAC mRNA and RAP1-GTP protein correlate with better diseases free survival of patients with primary melanoma. RNAseq analysis of patient-matched primary and metastatic melanoma cells treated with EPAC inhibitor ESI-09 revealed that TXNIP, an important regulator of redox homeostasis, is a downstream effector of EPAC-RAP1 signaling. Our data also show that EPACs promote melanoma growth by regulation of redox homeostasis and mitochondrial reactive oxygen species through activation of mechanistic target of rapamycin complex 1 (mTORC1) that stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), a transcriptional activator of TXNIP and glycolytic enzymes. Our data suggest that targeting mechanisms that metastatic melanoma cells employ to bypass EPAC dependency as a potential therapeutic approach for melanoma. Graphical Abstract

  PublisherOA PDFDOI

• SatTCR: a pipeline for performing saturation analysis of the T cell receptor repertoire and a case study of a healthy canine

  MethodsX · 2025-11-27

  articleOpen access

  Motivation: Profiling the T cell receptor (TCR) repertoire using next-generation sequencing (NGS) to quantify adaptive immune responses has become common in human and animal research. Companion dogs with spontaneous tumors have similarities with humans who have cancer. T cells undergo clonal expansion when they recognize specific antigens via surface TCRs. TCR counts from NGS data provide a way to quantify T cell response to vaccines, cancer, or infectious diseases for preclinical and clinical health studies. One complication is that the power and accuracy of TCR experiments depend substantially on the TCR sequencing depth, therefore it is important to determine the optimal read depth of an experiment to verify whether a subject's repertoire is correctly represented. Results: The optimal TCR sequencing depth for future experiments can be determined by randomly sampling lower TCR sequencing depths from a sequencing experiment, assembling the TCR clonotypes, and determining where the saturation of power and accuracy occurs. Moreover, one can determine whether an existing experiment has sufficient sequencing depth to justify its conclusions. We provide guidelines to determine whether the sequencing depth is adequate and a computational pipeline that:Samples pairs of sequences and assembles clonotypesSummarizes the results in a parametrized report.

  PublisherDOI

• Sattcr: A Pipeline for Performing Saturation Analysis of the T Cell Receptor Repertoire and a Case Study of a Healthy Canine

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease

  Annals of Clinical and Translational Neurology · 2025-12-09

  articleOpen access

  OBJECTIVE: Clinical trials for Huntington's disease (HD) enrolling persons before clinical motor diagnosis (CMD) lack validated biomarkers. This study aimed to conduct an unbiased discovery analysis and a targeted examination of proteomic biomarkers scrutinized by clinical validation. METHODS: Cerebrospinal fluid was obtained from PREDICT-HD and ancillary studies. Cohorts included HD family members who were gene-tested and considered prodromal following neuroexam. An initial unbiased mass spectrometry proteomics analysis identified candidate disease biomarkers that were then added to a targeted mass spectrometry assay including 100+ proteins associated with other neurodegenerative diseases. This assay determined relative quantifications of proteins in a single analysis. Significant biomarkers were examined against genetic and clinical measures of disease onset and progression. RESULTS: Two overlapping targeted analyses using 180 samples from 125 participants (61% female, 89% White, average age of 42 ± 14) were performed; longitudinal duration was 1-4 years. Based on participants' clinical data, 25 proteins correlated significantly with CAG-age-product (CAP) score and Unified HD Rating Scale (UHDRS) motor and cognitive measures. While most proteins increase in abundance with disease progression, proenkephalin and prodynorphin were downregulated before CMD. Power was low for longitudinal analysis. However, the reliability of HD family normal controls indicates that each individual's proteome remains relatively stable over time. INTERPRETATION: Findings replicate and extend the verification of HD biomarkers. Monitoring proenkephalin and prodynorphin levels in persons with HD may facilitate early detection and disease-tracking. These disease-specific biomarkers may improve the rigor of therapeutic intervention before clinical motor diagnosis. Further studies emphasizing longitudinal changes are needed to assess disease-monitoring. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00051324.

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• SOX5 IS A CRITICAL REGULATOR OF LINING SYNOVIAL FIBROBLAST FATE, FUNCTION, AND PATHOLOGY

  Osteoarthritis and Cartilage · 2025-04-01

  article
  PublisherDOI

• Atovaquone-induced oxidative stress activates the pentose phosphate pathway and Immunogenic cell death in ovarian cancer

  Scientific Reports · 2025-11-24 · 2 citations

  articleOpen access

  Atovaquone, an FDA-approved oxidative phosphorylation (OXPHOS) inhibitor, has shown promise in the treatment of epithelial ovarian cancer (EOC), the deadliest gynecologic malignancy. However, the precise mechanisms underlying its antitumorigenic effects remain unclear. We employed a longitudinal transcriptomic approach to characterize the molecular effects of atovaquone on EOC cells. Our findings demonstrate that atovaquone disrupts cellular homeostasis and metabolism, activates stress responses, and primes immune recognition. We observed temporal downregulation of genes and pathways involved in key cellular processes, such as the cell cycle and DNA replication, which correlated with reduced proliferative capacity. Atovaquone also downregulated both OXPHOS and glycolysis while upregulating the pentose phosphate pathway, suggesting a metabolic shift toward redox homeostasis restoration in response to severe oxidative stress. Consistent with oxidative stress, we found that atovaquone activated endoplasmic reticulum (ER) stress, which is linked to immunogenic cell death. During ER stress, calreticulin, a damage-associated molecular pattern (DAMP), translocates to the plasma membrane, where it promotes immune recognition. We observed that calreticulin was upregulated on the plasma membrane of atovaquone-treated EOC cells. Additionally, we detected increased levels of other DAMPs, such as high mobility group box 1 (HMGB1) and mitochondrial transcription factor A (TFAM), in the supernatants of atovaquone-treated cells, indicating the release of immunogenic molecules. Moreover, increased expression of ligands for activating receptors of NK cells was observed, and coculture experiments revealed enhanced NK cell activity toward atovaquone-treated cells. These results highlight atovaquone's potential to activate immune responses, offering a new avenue for combination therapies in EOC treatment.

  PublisherOA PDFDOI

• Winning at the Strategic Seams

  SSRN Electronic Journal · 2025-01-01

  articleOpen access1st authorCorresponding
  PublisherDOI

• Abstract 7237: Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection

  Cancer Research · 2025-04-21

  article

  Abstract Squamous cell carcinoma (SCC) development in mammals is thought to require months or years from the time that initial changes occur. We show that SCCs induced by the mouse papillomavirus MmuPV1, which are generally diagnosed 4-6 months post infection, can be found as soon as 2 weeks post infection. SCCs developed within 2 weeks in immune-competent, adult FVB (FVB/NTac) mice at sites prone to human papillomavirus (HPV)-induced tumors and cancers in human patients: the base of the tongue, the anus, and the skin. The anterior tongue, less susceptible than the base of the tongue to HPV-induced cancer in humans, was resistant to rapid-onset cancer. The presence of invasive cancer in histological tissue sections was verified by multiple pathologists. These diagnoses were corroborated by the results of a classic test of malignancy: skin tumors obtained two weeks post infection grew ectopically as subcutaneous grafts in immune-deficient hosts. Preventative treatment with a novel BRD4 inhibitor dramatically reduced the frequency of ear skin SCCs present 2 weeks post infection and significantly reduced overall disease severity. Like many human papillomaviruses, MmuPV1 lacks an E5 gene. Expression of HPV16 E5 driven by the Keratin 14 promoter in FVB mice (FVB/NTac-Tg(KRT14-HPV16E5*)33Plam/Plam) significantly increased the frequency of rapid-onset invasive cancers caused by MmuPV1 at the base of the tongue and in the anus. In an E5-transgenic mouse with a persistent MmuPV1-induced ear skin lesion, we detected a lymph node metastasis at 38 weeks - further demonstrating a cancer phenotype. Cancers and less severe dysplasia induced by infection at the base of the tongue or the anus spontaneously regressed within 4 to 8 weeks of infection; however, ear lesions persisted. When CD4+ and CD8+ T cells were depleted, lesions at the base of the tongue and anus also persisted, indicating that spontaneous regression involves a T cell-mediated immune response. These results indicate that papillomavirus infection alone is sufficient to induce rapid onset of invasive cancer, and that persistence of disease depends on the tissue-specific immune microenvironment. Citation Format: Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Shwu-Yuan Wu, Michael A. Newton, Cheng-Ming Chiang, Darya Buehler, Kristina Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert. Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7237.

  PublisherDOI

• Winning at the Strategic Seams

  2024-04-30

  book-chapter1st authorCorresponding

  Abstract International law exists to buttress rule-based relationships between sovereign States. Grey zone conflicts threaten these foundations. The current array of grey zone conflicts and asymmetric disputation erodes Western responses to threats, while corroding the very legal norms that bind modern international institutions. This chapter argues that democracies must learn to ‘win at the seams’ of the law to forestall a new epoch of international norms that warps their values. The chapter reimagines approaches for States seeking to preserve the rule of law and respect for human rights. It reassesses valuable insights drawn from the Principles of War to provide a model for preserving the institutional design of modern international law. Relying on the clean hands doctrine, the chapter recommends a more effective approach to counter States seeking to sow indecision and doubt amongst liberal democracies.

  PublisherDOI

Recent grants

• NIH Grant T32GM074904

  NIH · $1.5M · 2014

• NIH Grant R21HG006568

  NIH · $356k · 2015

• Cancer Center Administration

  NIH · $99.8M · 1997–2028

• NIH Grant R01CA064364

  NIH · $695k · 2009

• NIH Grant R29CA064364

  NIH · $494k · 2000

Frequent coauthors

• Linda Clipson

  90 shared

• Kristina A. Matkowskyj

  Mayo Clinic in Arizona

  68 shared

• Dustin A. Deming

  University of Wisconsin Carbone Cancer Center

  66 shared

• Richard B. Halberg

  University of Wisconsin–Madison

  65 shared

• Paul Ahlquist

  Morgridge Institute for Research

  61 shared

• Mark R. Albertini

  University of Wisconsin Carbone Cancer Center

  60 shared

• Irene M. Ong

  University of Wisconsin–Madison

  49 shared

• Cheri A. Pasch

  University of Wisconsin–Madison

  41 shared

Education

• Ph.D., Biostatistics

  University of Wisconsin-Madison

  1994

• M.S., Statistics

  University of Wisconsin-Madison

  1989

• B.S., Mathematics

  University of Wisconsin-Madison

  1986