- Biomedical Sciences Graduate Program | Melanie Rutkowski

Melanie Rutkowski

Primary Appointment

  • Assistant Professor, Microbiology, Immunology, and Cancer Biology

Contact

Research Interest(s)

Influence of commensal microbes on immune homeostasis, anti-tumor immunity, and metastasis

Research Description

Humans are colonized with trillions of microorganisms, collectively termed the microbiota. Aside from providing a first line of defense to invading pathogens or aiding in digestion and metabolism, commensal microbes are indispensable for the development of systemic inflammatory immune responses. The question is whether these microorganisms can directly influence diseases associated with systemic inflammation, such as cancer. Recently, we have shown that commensal microbes modulate systemic tumor-promoting inflammation by facilitating crosstalk between the immune system and a tumor developing outside of the intestines (Rutkowski et al. Cancer Cell, 2015). This was due, in part, to TLR5-mediated differences within the composition of commensal microbes in addition to tumor-induced inflammation.

We are currently interested in extending these studies further, so that we can understand how crosstalk between the commensal microbiome and immune system influence tumor initiation, growth, and metastatic dissemination. Our lab is interested in two major areas:

1) How do commensal microbes influence tumor growth and metastasis?

Tumor initiation, growth, and metastatic dissemination are dynamic processes that are influenced by local and systemic factors, including changes to commensal microbes. We have developed a breast cancer model where we can deliberately perturb the commensal ecosystem to attenuate metastatic disease, allowing the characterization of cellular and molecular factors within the tumor microenvironment that facilitate early dissemination and metastatic spread of breast tumor cells. Other projects are focused towards the identification of commensal-modulated immune or metabolic factors that impact tumor progression and metastatic disease in both ovarian and breast cancer, using transgenic mice and in vivo Crispr/Cas9 genome editing. The overarching goal for these projects is to leverage our discoveries towards the development of strategies that enhance anti-tumor immune responses or that alleviate immune-suppressive inflammation.

2) How do tumors influence the immune homeostasis at barrier surfaces?

We are also interested in understanding in how extraintestinal tumors influence the immune homeostasis at mucosal surfaces, with a focus upon characterizing innate immune changes. Projects include defining a role for exosomes in modulating the systemic immune environment and developing strategies that synergize with using checkpoint inhibitor therapy for the treatment of advanced hormone receptor+ breast cancer and for ovarian cancer. We are also characterizing how changes within the composition of commensal microbes might provide early biomarkers for developing tumors or for advanced metastatic disease and whether changes occurring at mucosal surfaces can predict responsiveness to immunotherapy. By combining mouse models with analysis of human specimens, our goal is to re-engineer the systemic immune environment of individuals with cancer through the restoration of commensal homeostasis to enhance treatment of metastatic disease.

The Rutkowski lab is accepting graduate students from the BIMS and MSTP programs.

http://bims.virginia.edu/

https://mstp.med.virginia.edu/

Selected Publications

  • Tesone A, Rutkowski M, Brencicova E, Svoronos N, Perales-Puchalt A, Stephen T, Allegrezza M, Payne K, Nguyen J, Wickramasinghe J, Tchou J, Borowsky M, Rabinovich G, Kossenkov A, Conejo-Garcia J. Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells. Cell reports. 2016. PMID: 26876172
  • Cubillos-Ruiz J, Silberman P, Rutkowski M, Chopra S, Perales-Puchalt A, Song M, Zhang S, Bettigole S, Gupta D, Holcomb K, Ellenson L, Caputo T, Lee A, Conejo-Garcia J, Glimcher L. ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. Cell. 2015;161(7): 1527-38. PMID: 26073941 | PMCID: PMC4580135
  • Rutkowski M, Allegrezza M, Svoronos N, Tesone A, Stephen T, Perales-Puchalt A, Nguyen J, Zhang P, Fiering S, Tchou J, Conejo-Garcia J. Initiation of metastatic breast carcinoma by targeting of the ductal epithelium with adenovirus-cre: a novel transgenic mouse model of breast cancer. Journal of visualized experiments : JoVE. 2014;. PMID: 24748051 | PMCID: PMC4027029
  • Rutkowski M, Stephen T, Svoronos N, Allegrezza M, Tesone A, Perales-Puchalt A, Brencicova E, Escovar-Fadul X, Nguyen J, Cadungog M, Zhang R, Salatino M, Tchou J, Rabinovich G, Conejo-Garcia J. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer cell. 2014;27(1): 27-40. PMID: 25533336 | PMCID: PMC4293269
  • Stephen T, Rutkowski M, Allegrezza M, Perales-Puchalt A, Tesone A, Svoronos N, Nguyen J, Sarmin F, Borowsky M, Tchou J, Conejo-Garcia J. Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity. 2014;41(3): 427-39. PMID: 25238097 | PMCID: PMC4174366
  • Scarlett U, Rutkowski M, Rauwerdink A, Fields J, Escovar-Fadul X, Baird J, Cubillos-Ruiz J, Jacobs A, Gonzalez J, Weaver J, Fiering S, Conejo-Garcia J. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. The Journal of experimental medicine. 2012;209(3): 495-506. PMID: 22351930 | PMCID: PMC3302234