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
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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.
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.
