Address

Henry Ford Health 2799 W Grand Blvd E&R 7067 Detroit MI 48202

Research Interests

• Cellular interactions (fibroblast-endothelial-immune-tumor cell) in the pancreatic cancer tumor microenvironment
  
• Investigation of Slit-Robo signaling pathway in pancreatic cancer initiation and progression
  
• Immune suppression and multi-omics data analysis of human pancreatic cancer
  
• Single cell RNA-sequencing (scRNAseq) atlas and spatial transcriptomics of mouse and human pancreatic cancer

 

Research Description

The Steele laboratory is a combined wet and dry lab focused on interrogation of signaling pathways disrupted in pancreatic cancer. Pancreatic cancer is poised to become the second leading cause of cancer related deaths worldwide by 2030. It is characterized by a highly complex and unique stromal reaction, and we are actively investigating how different cells communicate to drive tumor growth. The Steele lab uses data mining approaches to generate hypotheses in multi-omic datasets including dissociated scRNAseq, Visium spatial transcriptomics, Xenium in situ multiplex data, and high dimensional cytometry time-of-flight (CyTOF) from the mouse and human pancreas. We have several key areas of focus utilizing these techniques in addition to mechanistic mouse models of pancreatic cancer and in vitro co-culture systems.

One major focus of the lab is interrogating the functional role of the Slit-Robo pathway members in pancreatic cancer. This developmental axon guidance signaling pathway is crucial for midline crossing during formation of the spinal cord. This pathway is highly mutated (as well as changes in gene expression) in pancreatic cancer, the result of which remains unclear. We specifically investigate the functional roles of both Slit ligands expressed in the pancreas, Slit2 and Slit3 using cell type specific inducible Cre mouse models, as well as the role of one of the key receptors, Robo4. As high Robo4 expression correlates with improved survival in pancreatic cancer, one of the long-term goals for the Steele lab is to leverage Slit-Robo modulators in order to more effectively treat pancreatic cancer.

It is well established the tumor microenvironment of pancreatic cancer is highly immune suppressive. A second focus of the lab centers around understanding why pancreatic cancer patients do not respond to immunotherapy treatments. We have developed biomarker assays for major immune checkpoints, including TIGIT, LAG3, HAVCR2 and others, that are optimized for fine needle biopsies and resected tissues from both primary and metastatic pancreatic tumors, enabling for stratification of individualized immune-targeting treatments. A second focus of the lab interrogates the role of several subsets of rare but important T cells that have characteristics of both innate and adaptive immunity. We specifically evaluate the role of these cells in liver metastases of pancreatic cancer. The Steele lab combines big data driven approaches in human tissues to directly influence what mechanistic projects we undertake to ensure our research questions are relevant to human disease. 

Recent Publications

Yan W, Steele N, Kemp S, Menjivar R, Du W, Carpenter E, Donahue K, Brown K, Irizarry-Negron V, Yang S, Burns W, Zhang Y, Pasca di Magliano M, Bednar F. Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer. Clin Can Res. 2023;11:523584.

Carpenter E, Kadiyala P, Elhossiny A, Kemp S, Li J, Steele N,… KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment. Clin Can Res. 2023 Oct 18. 

Cornwell A, Tisdale A, Venjat S, Maraszek, Alahmari A, George A, Attwood K, George M, Rempinksi D, Franco-Barraza J, Parker M, Gomez E, Fountzilas C, Cukierman E, Steele N, Feigin M. Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer. Clin Can Res. 2023;29:3793-3812. 

Steele N⁺, Biffi G⁺, Kemp, S, Zhang Y, Drouillard, D., Syu, L, Hao, Y, Oni, T.E., Brosnan E, Elyada E, Doshi A, Hansma C, Espinoza C, Abbas A, The S, Irizarry-Negron V, Halbrook C, Franks N, Hoffman M, Brown K, Carpenter E, Nwosu Z, Johnson C, Lima F, Anderson M, Park Y, Crawford H, Lyssiotis C, Frankel T, Rao A, Bednar F, Dlugosz A, Preall J, Tuveson D‡, Allen B‡, Pasca di Magliano M‡, Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer. Clin Cancer Res. 2021;27:2023-37.

Steele N⁺, Carpenter E⁺, Kemp S⁺, Sirihorachai V⁺, The S, Delrosario, Lazarus L, Amir, E, Gunchick V, Paglia D, Macchia J, Chu A, Schofield H, Wamsteker E, Kwon R, Schulman A, Prabhu A, Law R, Sondhi A, Yu J, Patel A, Donahue K, Nathan H, Cho C, Anderson M, Sahai V, Lyssiotis C, Zou W, Allen B, Rao A, Crawford H‡, Bednar F‡, Frankel T‡, Pasca di Magliano M‡. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nature Cancer. 2020;1:1097-112. 

Brannon A+, Drouillard D+, Steele N+, Schoettle S, Abel E, Crawford H, Pasca di Magliano M. Beta 1 Integrin Signaling Mediates Pancreatic Ductal Adenocarcinoma Resistance to MEK Inhibition. Scientific Reports. 2020;10:11133.

Hutton C, Banyard A, Kononov A, Zhang X, Karim S, Paulus-Hock V, Heider F, Steele N, Kemp S, Jackstadt R, Iopes F, Menotti M, Chisholm L, Tr C, Valle J, Sansom O, Springer Z, Malliri A, Marais R, Pasca di Magliano M, Zelenay S, Morton J, Jorgenson C. Mass cytometry identifies two distinct fibroblast lineages in pancreatic tumors that differentially regulate antitumor immunity. Cancer Cell. 2021;39:1227-44.

Kemp S, Carpenter E, Nwosu Z, Steele N, Donahue K, Pacheco A, Velez-Delgado A, Menjivar R, Lima F, The S, Espinoza C, Long D, Zhang Y, Lyssiotis C, Rao A, Pasca di Magliano M‡, Crawford, H‡. Apolipoprotein E promotes immune suppression through NF-kB mediated Cxcl1 production in pancreatic cancer. Cancer Research. 2021;81:4305-18.

Zhang Y, Lazarus J, Steele N, Lee H, Yan W, Halbrook C, Menjivar R, Kemp S, Sirihorachai V, Carpenter E, Nevison A, Vinta A, Crawford H, Lyssiotis C, Frankel T, Bednar F, Pasca di Magliano M. Regulatory T cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis. Cancer Discovery. 2020;10:422-39.

Steele N, Chakrabarti J, Wang J, Biesiada J, Holokai L, Chang J, Nowacki LM, Hawkins J, Mahe M, Sundaram N, Shroyer N, Medvedovic M, Helmrath M, Ahmad S, Zavros Y. An Organoid-Based Preclinical Model of Human Gastric Cancer. Cell Mol Gastroenterol Hepatol. 2019;7:161-84.

Education/Training

Postdoc in pancreatic cancer (completed in 2022, University of Michigan, Ann Arbor MI)
PHD in Physiology and Systems Biology (completed in 2017, University of Cincinnati, Cincinnati OH)
Bachelor in Science (completed in 2012, Xavier University, Cincinnati OH)

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