Cancer is the second leading cause of death but, unlike heart disease, it has been a difficult disease to effectively understand or treat. The reason relates to the complexity and heterogeneity of the disease. Most tumors have complicated origins and are driven by rare mutations. Furthermore, different tissues have distinct cancers, individual tissues have multiple cancer subtypes, and tumors are composed of cells that are both genetically and phenotypically diverse. Thus, every tumor is unique and dynamic. The cause of lethality in most solid tumors such as breast cancer is the metastatic dissemination of tumor cells throughout the body. Metastasis is characterized by many distinct properties that are driven by changing stresses in the tumor microenvironment. Underlying all of these events are subcellular signaling pathways within tumor and environmental cells that are ultimately responsible for driving cells to a tumorigenic state.
The current focus of my laboratory is to understand fundamental signaling mechanisms leading to the generation of tumor cells and their progression to metastatic disease, particularly in triple-negative breast cancer that lacks targeted therapies. We use systems level approaches including activity-based proteomics, RNAseq, ChIPseq, and mass spectrometry as well as computational, molecular, biophysical, cellular and mouse model-based methodologies to identify and characterize key regulators of tumor growth and metastasis. As an additional tool, we have utilized a specific physiological suppressor of metastasis, Raf Kinase Inhibitory Protein (RKIP or PEBP1), and a downstream target of RKIP in cells, BACH1, to identify both molecular and cellular mediators of metastasis.
Our recent studies have shown that regulators of metastasis control multiple processes within the tumor cell microenvironment including metabolism, redox state, extracellular matrix, and recruitment and programming of tumor-associated macrophages. These factors also direct extracellular vesicles (exosomes) secreted by tumor cells to reprogram other cells in the body toward a pro-metastatic phenotype. Correlating omic-generated data from these studies with clinical data from cancer patients led to the identification of novel signaling modules that we used to build gene signatures that predict the metastatic potential of a tumor. More recently, our studies have led us to potential therapeutic treatments based on the concept of targeting key regulators of tumorigenesis, mimicking the action of metastasis suppressors such as RKIP or reprogramming signaling networks in cells to sensitize tumors to therapeutic agents.
Massachusetts Institute of Technology
Cambridge, MA
Instructor - Biochemistry/MolBio
1982
Massachusetts Institute of Technology
Cambridge, MA
Postdoctoral Fellow - Biochemistry/MolBio
1981
Massachusetts Institute of Technology
Cambridge, MA
Ph.D. - Biochemistry
1978
Harvard University
Cambridge, MA
AB - Biochemistry
1972
Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.
Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors. Nat Chem Biol. 2024 Aug 30.
PMID: 39215099
Nonmonotone invasion landscape by noise-aware control of metastasis activator levels.
Nonmonotone invasion landscape by noise-aware control of metastasis activator levels. Nat Chem Biol. 2023 07; 19(7):887-899.
PMID: 37231268
SARS-CoV-2 Diverges from Other Betacoronaviruses in Only Partially Activating the IRE1a/XBP1 Endoplasmic Reticulum Stress Pathway in Human Lung-Derived Cells.
SARS-CoV-2 Diverges from Other Betacoronaviruses in Only Partially Activating the IRE1a/XBP1 Endoplasmic Reticulum Stress Pathway in Human Lung-Derived Cells. mBio. 2022 10 26; 13(5):e0241522.
PMID: 36125275
SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1a/XBP1 ER stress pathway in human lung-derived cells.
SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1a/XBP1 ER stress pathway in human lung-derived cells. bioRxiv. 2022 Jun 13.
PMID: 35821981
Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop.
Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop. Proc Natl Acad Sci U S A. 2022 06 21; 119(25):e2121867119.
PMID: 35696587
Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses.
Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv. 2022 Feb 25; 8(8):eabi6110.
PMID: 35050692
Harnessing RKIP to Combat Heart Disease and Cancer.
Harnessing RKIP to Combat Heart Disease and Cancer. Cancers (Basel). 2022 Feb 09; 14(4).
PMID: 35205615
New strategies for targeting kinase networks in cancer.
New strategies for targeting kinase networks in cancer. J Biol Chem. 2021 10; 297(4):101128.
PMID: 34461089
Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5.
Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5. Cancers (Basel). 2021 Jul 10; 13(14).
PMID: 34298673
Limited inhibition of multiple nodes in a driver network blocks metastasis.
Limited inhibition of multiple nodes in a driver network blocks metastasis. Elife. 2021 05 11; 10.
PMID: 33973518
Fellow, American Association for the Advancement of Science (AAAS)
University of Chicago
2014 - 2014
Gerald N Wogan Prize Lecture, Massachusetts Institute of Technology
University of Chicago
2011 - 2011
Quantrell Award for Excellence in Undergraduate Teaching (Cancer Biology)
University of Chicago
2001 - 2001
Fellow, Institute of Medicine of Chicago
University of Chicago
1999 - pres
Quantrell Award for Excellence in Undergraduate Teaching, (Cell Biology)
University of Chicago
1991 - 1991
International Life Sciences Institute Research Foundation Award
MIT
1986 - 1986
American Cancer Society Postdoctoral Fellowship
MIT
1978 - 1980
Inst. National Research Service Award
MIT
1975 - 1977
Sloan Research Traineeship (Biophysics)
MIT
1973 - 1975
MIT Endowed Fellowship
MIT
1972 - 1972