Andy J. Minn, M.D., Ph.D.

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Associate Professor of Radiation Oncology
Department: Radiation Oncology

Contact information
Abramson Family Cancer Research Institute
421 Curie Blvd
BRB II/III, Room 510
Philadelphia, PA 19104
Education:
BA (Biology)
The University of Chicago, Chicago, IL, 1992.
PhD (Immunology)
The University of Chicago, Chicago, IL, 1999.
MD (Medicine)
The University of Chicago, Chicago, IL, 2000.
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Description of Research Expertise

KEYWORDS: Therapy resistance, metastasis, microenvironment, exosomes, immune checkpoint blockade, pattern recognition receptors, anti-viral signaling, bioinformatics, genomics, breast cancer, melanoma, glioblastoma multiforme.

RESEARCH INTERESTS:
My laboratory is interested in gene programs and signaling pathways discovered through unbiased high-dimensional data analysis that regulate cancer metastasis and its resistance to either conventional treatment or immune therapies. In particular, we are focusing on 1) how stromal cells orchestrate cancer therapy resistance, inflammation, and tumor progression, and 2) how tumor cells regulate an immune suppressive microenvironment to influence response to immunotherapies such as immune checkpoint blockade.

RESEARCH DETAILS:
The two most daunting obstacles in the clinical management of cancer are metastasis, or the spread of tumor cells from its origin to distant sites in the body, and resistance to therapy. Unfortunately, the molecular mechanisms that drive these central and elusive problems in oncology have remained poorly understood.

Our laboratory is focused on understanding how cancer cells acquire metastatic and treatment resistant phenotypes. Recent evidence suggests that these traits are acquired during tumorigenesis by antagonistic forces encountered as tumors grow and interact with their environment. Key among these selective pressures include inflammation, immune responses, and barriers imposed by surrounding stroma. Because the biology of these selective pressures can overlap with molecular mechanisms involved in treatment resistance and metastasis, genetic alterations that occur as a response to these pressures may predispose tumors to acquire a aggressive features of cancer. Accordingly, we have a particular focus on how tumor cells interact with the microenvironment (stromal cells, immune cells) and the consequences of these interactions.

In order to better understand mechanism and disease-relevance, we utilize a multi-disciplinary approach towards both experimental and translational research goals. Hypothesis generation and testing relies on a systems biology paradigm that incorporates animal models, molecular biology, high-dimensional data analysis, bioinformatics, and clinical correlation. Using these methods we and colleagues have identified gene programs and signaling pathways that not only predict but also regulate cancer phenotypes such as aggressive organ-selective metastasis, resistance to conventional therapies (chemotherapy and radiation), and resistance to immunotherapies. Some of these gene programs and pathways are expressed across multiple common human cancers including breast cancer, brain cancer, and melanoma, suggesting their disease relevance.

Mechanistic dissection of computational predictions have uncovered novel and complex signaling pathways on how tumor cells communicate with their microenvironment. One example includes how endogenous non-coding RNAs packaged in exosomes are transferred from stromal to breast cancer cells to engage therapy resistance pathways, or immune cells to cause an inflammatory response. These RNAs activate pattern recognition receptors that engage interferon-related pathways and indirectly stimulate juxtacrine signaling through NOTCH receptors. Another example includes how tumor cells can alter the immune microenvironment to dictate the effectiveness of immune therapies such as immune checkpoint blockade. Intriguingly, this can also involve interferon signaling in tumor cells whereby prolonged stimulation (as can occur in disease contexts such as cancer) results in epigenetic and transcriptomic rewiring that enforces a multigenic immunosuppressive program. This resistance program renders tumors cells resistant to multiple immunotherapies. In all cases, the gene programs and pathways uncovered not only provide insight into important biological mechanisms but also provide potential biomarkers for prognosis, prediction, and therapy.

ROTATION PROJECTS:
Many rotation projects related to the research interests described are available. Please contact Dr. Minn to inquire.

LAB PERSONNEL:
Taewon Yoon, Senior lab manager
Lex Johnson, Graduate student
Bihui Xu, Graduate student
Erica Dhuey, Graduate student
Joseph Benci, Postdoc
Lisa Cucolo, Graduate student
Jacob Shabason, Instructor
Shetal Patel, Fellow
Brian Kim, Research technician
Olivia Oldridge, Research specialist
Jingya Qiu, Graduate student

Selected Publications

Nabet Barzin Y, Qiu Yu, Shabason Jacob E, Wu Tony J, Yoon Taewon, Kim Brian C, Benci Joseph L, DeMichele Angela M, Tchou Julia, Marcotrigiano Joseph, Minn Andy J: Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer. Cell 170(2): 352-366.e13, Jul 2017.

Benci Joseph L, Xu Bihui, Qiu Yu, Wu Tony J, Dada Hannah, Twyman-Saint Victor Christina, Cucolo Lisa, Lee David S M, Pauken Kristen E, Huang Alexander C, Gangadhar Tara C, Amaravadi Ravi K, Schuchter Lynn M, Feldman Michael D, Ishwaran Hemant, Vonderheide Robert H, Maity Amit, Wherry E John, Minn Andy J: Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell 167(6): 1540-1554.e12, Dec 2016.

Minn Andy J, Wherry E John: Combination Cancer Therapies with Immune Checkpoint Blockade: Convergence on Interferon Signaling. Cell 165(2): 272-5, Apr 2016.

Twyman-Saint Victor Christina, Rech Andrew J, Maity Amit, Rengan Ramesh, Pauken Kristen E, Stelekati Erietta, Benci Joseph L, Xu Bihui, Dada Hannah, Odorizzi Pamela M, Herati Ramin S, Mansfield Kathleen D, Patsch Dana, Amaravadi Ravi K, Schuchter Lynn M, Ishwaran Hemant, Mick Rosemarie, Pryma Daniel A, Xu Xiaowei, Feldman Michael D, Gangadhar Tara C, Hahn Stephen M, Wherry E John, Vonderheide Robert H, Minn Andy J: Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547): 373-7, Apr 2015.

Boelens Mirjam C, Wu Tony J, Nabet Barzin Y, Xu Bihui, Qiu Yu, Yoon Taewon, Azzam Diana J, Twyman-Saint Victor Christina, Wiemann Brianne Z, Ishwaran Hemant, Ter Brugge Petra J, Jonkers Jos, Slingerland Joyce, Minn Andy J: Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159(3): 499-513, Oct 2014.

Minn Andy J, Gupta Gaorav P, Siegel Peter M, Bos Paula D, Shu Weiping, Giri Dilip D, Viale Agnes, Olshen Adam B, Gerald William L, Massagué Joan: Genes that mediate breast cancer metastasis to lung. Nature 436(7050): 518-24, Jul 2005.

Jiang Yuchao, Qiu Yu, Minn Andy J, Zhang Nancy R: Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing. Proceedings of the National Academy of Sciences of the United States of America 113(37): E5528-37, Sep 2016.

Ishwaran Hemant, Kogalur Udaya B, Chen Xi, Minn Andy J : Random survival forests for high-dimensional data. Statistical Analysis and Data Mining 4: 115-32, Jan 2011.

Ishwaran Hemant, Kogalur Udaya B, Gorodeski Eiran Z, Minn Andy J, Lauer Michael S: High dimensional variable selection for survival data. Journal of the American Statistical Association 105: 205-17, Mar 2010.

Weichselbaum Ralph R, Ishwaran Hemant, Yoon Taewon, Nuyten Dimitry S A, Baker Samuel W, Khodarev Nikolai, Su Andy W, Shaikh Arif Y, Roach Paul, Kreike Bas, Roizman Bernard, Bergh Jonas, Pawitan Yudi, van de Vijver Marc J, Minn Andy J: An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proceedings of the National Academy of Sciences of the United States of America 105(47): 18490-5, Nov 2008.

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Last updated: 09/12/2017
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