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Josie Ursini-Siegel

Josie Ursini-Siegel, PhD

Cancer

Breast cancer, Immune suppression, Inflammation, Melanoma, Metabolic reprogramming, mRNA translation, Oxidative stress, Signal transduction, Transgenic mouse models
  • Scientific Director, Molecular Oncology Group, and Principal Investigator, Lady Davis Institute for Medical Research
  • Professor, Departments of Oncology and Biochemistry, McGill University

Contact details

(514) 340-8222 ext. 26557
giuseppina.ursini-siegel@mcgill.ca

Snapshot

Tumor heterogeneity contributes to the evolution of metastatic and hard-to-treat cancers along with the development of drug resistance. My laboratory seeks to better understand the mechanisms that promote this heterogeneity to prevent the development of metastatic disease and identify combination strategies to eradicate heterogeneous cancer cell populations to overcome the development of intrinsic/acquired resistance. Indeed, metastasis and relapse are largely mediated by increased plasticity. Solid cancers are composed of a mosaic of neoplastic cells, each with their own genetic alterations, and varying access to secreted proteins (growth factors, extracellular matrix), nutrients and oxygen, as well as fibroblasts, endothelial cells and immune cells. The goal of my program is to elucidate the mechanisms contributing to the emergence of aggressive and drug resistant cancers and expose targetable vulnerabilities to eradicate these hard-to-treat malignancies.

My research focuses on three research areas:

  • Understanding how dysregulated signal transduction pathways increase mRNA translation of tumor and metastasis-promoting proteins, contributing to the development of aggressive cancers.
  • Understanding the dual role of oxidative stress in cancer whereby moderately elevated reactive oxygen species (ROS) production increases the aggressive properties of cancers whereas severe and acute ROS exerts potent anti-neoplastic functions.
  • Understanding mechanisms that increase anti-tumor immunity. This includes strategies to increase the tumoricidal functions of both innate and adaptive immune cells as a therapeutic strategy to treat aggressive cancers.

We ultimately apply this knowledge to the development of rational combination approaches to shrink treatment-refractory and metastatic breast cancers and melanomas.

Read more

Important Links :

See Ursini-Siegel, Josie's publications on PubMed

Major Research Activities

Targeted therapies offer little to no survival benefit for individuals with hard-to-treat cancers, including metastatic and drug-resistant disease. The greatest hurdle to developing life-extending therapies for such hard-to-treat malignancies is the enormous amount of genetic diversity in each tumor, making “personalized” approaches targeting individual mutations next to impossible.

 

My research team addresses this unmet need by first interrogating the adaptive stress responses that all cancer cells must overcome to survive even under the harshest of conditions, making them more aggressive. Subsequently, we leverage this information to develop rational combination therapies that target these essential vulnerabilities with a goal to evoke potent anti-tumorigenic and anti-metastatic responses irrespective of the mutational landscape and heterogeneity of individual cancers. We focus on four such adaptive stress responses:

  • We seek to understand how the mRNA translation machinery is dysregulated in cancer cells and then to attenuate protein synthesis, representing a universal requirement for cancer cell growth, survival and metastasis.
  • We seek to understand how cancer cells adapt to and exploit reactive oxygen species (ROS) production, which are highly unstable oxygen containing molecules. We study the mechanisms by which chronic and moderate oxidative stress increases the aggressive properties of cancers. Leveraging this information, we seek to identify novel strategies to potentiate a more severe and acute oxidative stress, which instead confers tumoricidal responses.
  • We seek to understand how chronic inflammation increases the tumor- and metastasis-promoting properties of cancers and how we can reprogram these inflammatory responses to instead acquire tumor killing properties, focusing on novel innate immune cell subsets with tumoricidal functions.
  • We seek to understand how immune suppression leads to the emergence of aggressive cancers and then devise strategies to re-activate anti-tumor immune responses that sensitize tumors to immunotherapies.

To achieve these objectives, our highly collaborative team employs multi-disciplinary in vivo and in vitro approaches including mouse genetics, molecular biology studies, flow cytometry, confocal microscopy and several -omics based technologies (transcriptomics, proteomics, metabolomics). We focus primarily on aggressive breast cancer and melanoma.

 

 

Recent Publications and References