Sean Ronnekleiv-Kelly
Contact Information
ronnekleiv-kelly@surgery.wisc.edu
(608) 263-9792
600 Highland Ave
Madison, WI 53792
Education
MD, University of Colorado School of Medicine
General Surgery Residency, University of Wisconsin School of Medicine and Public Health
Complex General Surgical Oncology Fellowship, Johns Hopkins Hospital
Title
Associate Professor of Surgery
Research Description
Our Goals
- To understand how disruption of the circadian clock contributes to carcinogenesis and a more aggressive cancer phenotype in pancreas cancer.
- To determine how the DNAJB1-PRKACA fusion oncogene drives cancer formation to identify novel therapies for the spectrum of cancers caused by this gene fusion.
Our Projects
- We have identified the orphan monocarboxylate transporter, SLC16A14, as strongly linked to DNAJB1-PRKACA. SLC16A14 may play a key metabolic role in the cancer cells, and we are working towards understanding the structure of this protein as well as transport substance and function in DNAJB1-PRKACA expressing cells (i.e., de-orphanization).
- We have developed a novel platform to evaluate individual patient tumors (PDAC) and identify which patient PDAC harbors a disrupted circadian clock (BMAL1 suppressed) versus intact circadian clock. Those tumors with a disrupted clock and BMAL1 suppression portend a far worse prognosis. We use patient cancer-derived xenograft models, patient cancer-derived organoids and syngeneic mouse models to understand how BMAL1 silencing and circadian disruption occurs in human PDAC for prognostic and therapeutic avenues.
- We have identified CDK7 as a therapeutic target in DNAJB1-PRKACAdriven cancer. We are using patient cancer-derived models and engineered cell lines to identify top candidate drugs targeting CDK7, and advanced molecular techniques to determine why DNAJB1-PRKACA cancer cells are so susceptible to CDK7 inhibitor therapy. This has led to informed combination therapies that may be applied as a translational approach. We are also evaluating other cancer subtypes that are sensitive to CDK7 inhibitor therapy.
- We have constructed a conditional immune competent model of DNAJB1-PRKACA driven carcinoma that mimics human IOPN-associated carcinomas of the pancreas and bile duct. Using this model system, we aim to understand how the DNAJB1-PRKACA transformed cells remodel the tumor microenvironment to yield a permissive, desmoplastic stroma and invasive carcinoma development.
Recent Publications
- Single-Cell RNA Sequencing of Murine Liver Reveals an Aligned Circadian Clock and Cell-Population-Specific Circadian-Regulated Pathways.
Veltri AJ, Nukaya M, Korac K, Schwartz PB, Ronnekleiv-Kelly SM
J Biol Rhythms 2026 Jul 03; 7487304261453628
[PubMed ID: 42397025] - Identifying Novel Estrogenic Mitochondrial Targets in Hypothalamic Proopiomelanocortin Neurons by Chemoproteomics.
Qiu J, Bosch MA, Wolfe M, Korac K, Rizzo S, Stincic TL, Farley SE, Fitzgerald W, Rajendran M, Laguerre A, Stein F, Copenhaver PF, Rønnekleiv OK, Rønnekleiv-Kelly SM, Rostovtseva TK, Bezrukov SM, Schultz C, Kelly MJ
bioRxiv 2026 Jun 22;
[PubMed ID: 42395377] - The DNAJB1-PRKACA Oncogenic Fusion Drives Stepwise Biliary and Pancreatic Carcinogenesis from Intraductal Precursor Lesions.
Carney PR, Nukaya M, Carter JA, Veltri AJ, Matkowskyj KA, Stram A, Rubinstein CD, Veith AC, Pillarisetty VG, Bradfield CA, Ronnekleiv-Kelly SM
bioRxiv 2026 May 27;
[PubMed ID: 42244708] - Single-cell Transcriptomic Variance Analysis Reveals Intercellular Circadian Desynchrony in the Alzheimer’s Affected Human Brain.
Hollis HC, Veltri A, Korac K, Menon V, Bennett DA, Ronnekleiv-Kelly SM, Kim J, Anafi RC
bioRxiv 2026 Mar 25;
[PubMed ID: 41929229] - Correction: DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.
Ma RK, Tsai PY, Farghli AR, Shumway A, Kanke M, Gordan JD, Gujral TS, Vakili K, Nukaya M, Noetzli L, Ronnekleiv-Kelly S, Broom W, Barrow J, Sethupathy P
PLoS Genet 2026 Feb; 22(2): e1012054
[PubMed ID: 41746900]