Jennifer Isaacs, PhD
Director, Pharmacology Graduate Program
Director, Pharmacology MS Program
Member, Developmental Cancer Therapeutics Program
Hollings Cancer Center
1997 Ph.D., University of North Carolina Chapel Hill
Office: HO 712E
Cancer signaling and chromatin remodeling in tumor progresssion
Our research program is aimed at unraveling key mechanisms contributing to cancer progression. It is well known that tumor invasion and subsequent metastasis is a main cause of cancer lethality. However, not all tumors are inherently aggressive or even need to be treated. We utilize prostate cancer as a clinically relevant example of this phenomenon. Prostate cancer is the most frequently diagnosed male cancer and the second most lethal cause of cancer death among men. Despite this grim statistic, the majority of men diagnosed with prostate cancer die of non-cancer related causes. Our work is therefore focused upon defining the key events that distinguish indolent, or slow growing cancers, from those that transition to an aggressive state and require treatment.
Surprisingly, we have found that an atypical extracellular form of the Hsp90 chaperone is capable of triggering the switch to aggressive disease. Hsp90 is preferentially secreted by cancer cells and intriguingly, we find that more aggressive cancer cells exhibit enhanced secretion of Hsp90. This observation, coupled with our functional studies, strongly suggest that extracellular Hsp90 (eHsp90) executes a conserved pro-tumorigenic program. It is expected that our studies into eHsp90 action will: (i) reveal targetable vulnerabilities in prostate cancer, (ii) have functional relevance in additional tumor types, (iii) elucidate a conserved molecular circuitry capable of driving tumor progression.
As cancer is a complex system, we incorporate various disciples and utilize a number of experimental approaches. A main scientific focus is to understand how eHsp90 impacts the cancer cell. Towards this end, we enforce Hsp90 secretion in indolent tumor models, and conversely, pharmacologically block this pathway in aggressive cancers. We are dissecting the signaling events initiated by eHsp90, and following how these cues impact upon genetic and epigenetic pathways to control cell morphology, invasive potential, and cancer stemness. As a complementary focus, we are evaluating how eHsp90 impacts upon stromal cell types of the tumor microenvironment, given the established role of tumor stroma as an instigator of aggressive disease. We utilize relevant animal models, clinical specimens, and are in the process of generating a transgenic mouse model that will be invaluable in interrogating eHsp90 action in both development and disease.
For more information about the lab and specific projects, please view our lab website.
1. Gopal U, Bohonowych JE, Lema-Tome C, Liu A, Garrett-Mayer E, Wang B, Isaacs JS. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion. PLoS One. 2011 6(3):e17649. PMCID: PMC3050925
2. Hance MW, Dole K, Gopal U Bohonowych JE, Jezierska-Drutel A, Neumann CA, Liu H, Garraway IP, Isaacs JS. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J Biol Chem. 2012 287(45):37732-37744. PMCID: PMC3488049
3. Bohonowych JE, Hance MW, Nolan KD, Defee M, Parsons CH, Isaacs JS. Extracellular Hsp90 mediates an NF-κB dependent stromal inflammatory program: Implications for the tumor microenvironment. Prostate. 2014 74(4):395-407. PMCID: PMC4306584
4. Hance MW, Nolan KD, Isaacs JS. The double-edged sword: Conserved functions of extracellular Hsp90 in wound healing and cancer. Cancers. 2014 6(2):1065-1097. PMCID: PMC4074817
5. Nolan KD, Franco OE, Hance MW, Hayward SW, Isaacs JS. Tumor secreted Hsp90 subverts Polycomb function to drive prostate tumor growth and invasion. J Biol Chem. 2015 290(13):8271-8282. PMCID: PMC4375482
6. Jarosz DF, Isaacs JS. Hsp90 as a capacitor of epigenetic function: Implications for cellular and organismal plasticity. Advances in Cancer Research, Elsevier, In Press