Penina Brodt
Professor
B.Sc., M.Sc., Ph.D.
Overall Research Theme: Cancer Metastasis: molecular mechanisms and therapy
Specific Projects:
1) Role of the IGF-I receptor in liver metastasis: signaling and crosstalk with the microenvironment
2) The pro-metastatic microenvironment of the liver: role of inflammation and the immune tolerant microenvironment of the liver
3) Developing an IGF Trap for prevention of cancer growth and metastasis
4) Role of the pancreatic stroma exosomes in pre-metastatic niche formation in the liver
5) Optimizing drug delivery for the treatment of brain cancer
6) Role of IMP1 in pancreatic ductal adenocarcinoma progression
听
See website:
Bringing a drug candidate to the clinic for cancer treatment
We are studying molecular aspects of cancer metastasis. In this context, the roles of cell adhesion receptors, cytokines and growth factors in the regulation of angiogenesis, cancer cell invasion and metastasis are being investigated. The following projects are in progress.
A. The role of the type 1 Insulin-like growth factor receptor (IGF-1R) in metastasis.
We identified the IGF-I receptor as a regulator of tumor cell invasion and metastasis. Receptor domains with distinct contributions to the metastatic phenotype were identified. Presently, we are investigating signal transduction pathways involved in transcriptional regulation by IGF-IR, using a combination of approaches that include gene transfer, use of dominant negative mutants and promoter assays. The contribution of different receptor domains to transcriptional regulation of different genes is also being investigated. In parallel, the role of post internalization, receptor-ligand complex processing in signaling is being investigated.
B. Gene therapy of cancer metastases.
Multiple strategies are being developed for gene therapy of metastases based on targeting and disruption of IGF-IR synthesis and/or signaling. These strategies are being tested in several cancer types including colorectal carcinoma, breast carcinoma and brain tumors.
C. Tumor-endothelial cell interactions: role in liver metastasis.
We have shown that the endothelial cell adhesion receptor E-selectin mediates carcinoma cell adhesion to liver sinusoidal endothelial cells and liver metastasis (Khatib et al, Cancer Res. 62:2002). Presently, the molecular cascade that is initiated following tumor cell entry into the hepatic circulation is being investigated by a combination of听in vivo听and听in vitro听techniques. In particular, the roles of E-selectin, VCAM-1, PECAM-1 and ICAM-1 and of inflammatory cytokines and chemokines are being analysed. A combination of immunohistochemistry, fluorescence based techniques and molecular analyses if being used.
POSITIONS AND EMPLOYMENT
1979-1980 MRC Postdoctoral Fellow, Weizmann Institute of Science, Rehovot, Israel
1980-1982 MRC Postdoctoral Fellow, Dept. of Anatomy, 成人VR视频
1983-1991 Assistant Professor, Dept. of Surgery, 成人VR视频
1984-1989 Medical Research Council of Canada Scholar
1990-1993 Chercheur Boursier, Fonds de la Recherche en Sant茅 du Qu茅bec.
1992-2000 Associate Professor, Dept. of surgery and Oncology, 成人VR视频
1993-1994 Visiting Professor, Dana Farber Cancer Institute, Harvard Medical School, Boston, Mass
1997-2000 Associate Professor, Dept. of Medicine, 成人VR视频
2001- Professor - Departments of Surgery, Medicine & Oncology, 成人VR视频
2004-2005 Visiting Scientist - National Institute of Health, Bethesda MD
2005 Visiting Scientist鈥� Technion Institute of Technology - Haifa, Israel
2005 Joels Hebrew University Visiting Professor (on sabbatical leave)
2011- Senior Scientist 鈥� Research Institute of the 成人VR视频 Health Center
2013 Visiting Scholar - University of California San Diego, Department of Pharmacology
听
Personal Statement
The focus of my research program has been the biology of cancer metastasis. In this context, our work has centered on the role of the microenvironment (ME) in liver metastasis (LM) of GI cancers. Our overarching goal has been translational and our aim has been to identify targets and develop therapeutic interventions to block the spread of malignant disease to, and within the liver. In the course of these studies, our research team was among the first to show that cancer cells entering the liver induce a rapid inflammatory response resulting in a cytokine cascade that enables trans-endothelial migration and liver colonization. We also discovered that in this TNF-飦� rich ME, the metastatic cells can escape death through autocrine IL-6/STAT3 signaling. We identified The TNF receptor 2 (TNFR2) as a survival factor for regulatory T cells and myeloid-derived suppressor cells in the immune-tolerant ME (IME) of colon cancer LM. This work led to the identification of a sexual dimorphism in the control of the liver IME and the discovery of the important role that estrogen plays in this regulation. Our lab was also among the first to document the importance of the IGF-axis to cancer cell invasion and metastasis in general, and LM, in particular. Several strategies for targeting the IGF-axis were developed, leading to the bioengineering of the IGF-Trap - a potent inhibitor of growth and metastasis of several aggressive cancers including pancreatic ductal adenocarcinoma (PDAC). More recently, we discovered that the IGF-Trap affects the innate immune response to metastatic cells in the liver, blocking the polarization of infiltrating neutrophils and macrophages to an immunosuppressive phenotype and profoundly changing the immune landscape associate with LM. We subsequently optimized a combinatorial immunotherapy for the prevention and treatment of PDAC LM consisting of the IGF-Trap and anti PD-1 antibodies. In addition, our work on the biology of PDAC was recently extended to targeting a protein that drives PDAC progression (IMP-1) and our current work focuses on gaining mechanistic insight into its role in PDAC growth and metastasis.
BOOKS (2011-PRESENT ONLY)
Brodt P. (Ed): Liver Metastasis: Biology and Clinical Management 鈥揝pringer-Verlag Heidlberg, London, NY, 2011, ISBN: 978-94-007-0292
95) *Vaniotis G., *Rayes, RF., Qi, S., *Milette, S., Wang, S., Perrino, S., Nystr枚m, N., He Y., Lamarche-Vane N., and Brodt, P. Collagen IV-conveyed signals regulate chemokine production and promote liver metastasis. Oncogene 2018, Jul;37(28):3790-3805. doi: 10.1038/s41388-018-0242-z. Epub 2018 Apr 13.
96) *Vaniotis G., Moffett S., Sulea T., Wang N., Elahi SM., Lessard E., Baardsnes J., Perrino S., Durocher Y., Frystyk J., Massie B., and Brodt P. Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties. Sci Rep. 2018, Nov 26;8(1):17361. doi: 10.1038/s41598-018-35407-2
97) *Milette S., *Hashimoto M., P茅rrino S., *Qi S., *Chen M., *Ham B., Wang N., Lowy AM., Piccirillo C., and Brodt P., 2019, Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases. Nature Commun. 2019, Dec 17;10(1):5745. doi: 10.1038/s41467-019-13571-x.
98) *Chen Y.M., *Qi S., Perrino S., *Hashimoto M., and Brodt P. Targeting the IGF-axis for cancer therapy: Development and validation of an IGF-Trap as a potential drug. Cells 2020, Apr 29;9(5):1098. doi: 10.3390/cells9051098
100) *Qi S., Perrino S., Lamarche-Vane N. and Brodt P. The chemokine CCL7 regulates invadopodia maturation and MMP-9 mediated collagen degradation in liver-metastatic carcinoma cells. Cancer Lett. 2020, Jul 28;483:98-113. doi: 10.1016/j.canlet.2020.03.018. Epub 2020 Mar 23
104) Tsilimigras D.I., Brodt P., Clavien P.A., Muschel R.J., D鈥橝ngelica MI., Endo I., Parks R.W., Doyle M., de Santibanes E., and Pawlik T.M. Liver Metastases. Nature Reviews: Disease Primers 2021, Apr 15;7(1):27. doi: 10.1038/s41572-021-00261-6
105) Ciner A.T., Jones, K., Muschel R. and Brodt P. The unique immune microenvironment of liver metastases: Challenges and opportunities. Semin Cancer Biol. 2021, Jun;71:143-156. doi: 10.1016/j.semcancer.2020.06.003.
106) *Hashimoto M., *Konda J.D., Perrino S., *Fernandez M.C., Lowy A.M. and Brodt P. Targeting the IGF-axis potentiates immunotherapy for pancreatic ductal adenocarcinoma liver metastases by altering the immunosuppressive microenvironment. Mol Cancer Ther. 2021 Dec;20(12):2469-2482. doi: 10.1158/1535-7163. MCT-20-0144. Epub 2021 Sep 22.
108) *Chen Y.M., *Leibovitch M., Zeinieh M., Jabado N. and Brodt P. Targeting the IGF-axis in cultured pediatric high-grade glioma cells inhibits cell cycle progression and survival. Pharamaceuticals 16(2):297-310, 2023 doi: 10.3390/ph16020297.
