School of Dental Medicine Faculty

LYNN E. HEASLEY Professor   Craniofacial Biology Mail Stop 8120, RC1-S, Rm L18 11102 12801 E. 17th Ave. P.O. Box 6511 Aurora, CO 80045 Phone: 303-724-4578 Fax: 303-724-4580 Email: Click for Email

Education:
Ph.D. (Pharmacology), UC San Diego, La Jolla, CA

Postdoctoral Training:
Dept. of Biochemistry, University of Massachusetts Medical Center, Worcester, MA
Division Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO

Departmental Affiliations:
Craniofacial Biology, School of Dental Medicine
Department of Pharmacology, SOM

Graduate Program Affiliations:
Biomedical Sciences Program (BSP)
Medical Scientist Training Program (MSTP)
Pharmacology
Cancer Biology Program

Research Interests:
Role of the cJun N-terminal kinase (JNK) pathway in tumor cell biology. The JNK subfamily of mitogen-activated protein kinases (MAPKs), encoded by jnk1, jnk2 and jnk3, are broadly activated by growth factors and oncogenes as well as cell stresses and play both positive and negative roles in cellular transformation. Our experiments in JNK1 and JNK2-deficient mice reveal increased carcinogen-induced lung tumorigenesis compared to wild-type mice. Also, human lung cancer cell lines and primary tumors show decreased measures of JNK activity relative to non-transformed lung epithelial cells and normal lung samples. Thus, we propose that JNK1 and JNK2 are components of a novel tumor suppressor pathway operating downstream of specific Wnts and Fzds in lung cancer. By contrast, preliminary studies with JNK3-deficient mice show decreased carcinogen-induced lung tumorigenesis, suggesting that JNK3 is pro-tumorigenic in the setting of lung cancer. Thus, our findings support an hypothesis that JNKs function as both tumor suppressors and pro-tumorigenic signals in a context and JNK isoform-dependent manner and demonstrate that a detailed understanding of the multi-faceted role of the JNKs in lung cancer is imperative for logical and precise therapeutic targeting of this pathway in cancer cells.

Autocrine and paracrine signaling through polypeptide growth factors in cancer. Autocrine growth factor signaling, often through receptor tyrosine kinases (RTKs), is a hallmark of cancer cells. While EGF receptors (EGFRs) and the EGF family of ligands were thought to constitute a dominant autocrine pathway in human non-small cell lung cancer (NSCLC), only 10-20% of patients exhibit a clinical response to the EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Thus, consistent with the known heterogeneity of NSCLC, EGFR is not the only RTK mediating autocrine growth in lung cancer. Importantly, we have recently found that fibroblast growth factor 2 (FGF2), FGF9 and FGF receptors (FGFRs) are frequently co-expressed in NSCLC. Moreover, FGF2 shRNAs, dominant-negative FGFR1 and FGFR-selective TKIs (RO4383596, pazopanib) selectively reduce growth of NSCLC cell lines that co-express FGF2 or FGF9 and FGFRs. By contrast, cell lines lacking FGF2 expression are resistant to RO4383596 and sensitive to gefitinib. Beyond EGFR and FGFR-mediated autocrine signaling, other RTK systems will also likely be involved in lung cancer cells including IGF-1R and its ligands, IGF-1 and IGF-2. Finally, our preliminary data support a role for FGFR and EGFR loops in the induction of epithelial-mesenchymal transition (EMT), a program critical to tumor progression and metastasis. Together, our findings support an hypothesis that multiple RTK systems including EGFR, FGFR and IGF-1R function in cancer cells to drive cell transformation and EMT.

Selected Publications:
Levresse, V., Marek, L., Blumberg, D., and Heasley, L.E. (2002) Regulation of platinum compound cytotoxicity by the cJun N-terminal kinase and cJun signaling pathway in small cell lung cancer cells. Mol. Pharmacol. 62:689-697.

Winn, R.A., Marek, L., Han, S.Y., Rodriguez, K., Rodriguez, N., Hammond, M., Van Scoyk, M, Acosta, H., Mirus, J., Barry, N., Hurteau, G., Bren-Mattison, Y., Van Raay, T.J., Nemenoff, R.A., and Heasley, L.E. (2005) Restoration of Wnt-7a expression reverses non-small cell lung cancer cell transformation through frizzled-9 mediated growth inhibition and promotion of cellular differentiation. J. Biol. Chem. 280:19625-19634.

Heasley, L.E. and Han, S.Y. (2006) JNK regulation of oncogenesis. Mol Cells 21:167-173.
Winn, R.A., Van Scoyk, M., Hammond, M., Rodriguez, K., Crossno, J., Heasley, L.E., and Nemenoff, R.A. (2006) Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5 dependent activation of PPARg. J. Biol. Chem. 281:26943-50.

Marek, L., Fritzsche, A., Helton, W.R., Smith, J.E., McDermott, L.A., Coldren, C.D., Nemenoff, R.A., Merrick, D.T., Helfrich, B.A., Bunn, P.A., Jr., Merrick, D.T. and Heasley, L.E. Dominant FGF autocrine signaling in gefitinib-resistant non-small cell lung cancer cells. Submitted, J. Biol. Chem.

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