Page 37 - Hormel Institute Annual Report 2021-22

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VEGF-induced vascular permeability is reduced upon CRISPR/Cas9-mediated knockout of Stat3 in zebrafish.
A) Microangiography using 70 kDa Texas Red-dextran permeabilizing tracer (red) and 2000 kDa FITC dextran intersegmental vessel marker (green) was performed on 3 days post-fertilization Stat3+/+ (negative controls without VEGF induction; left), VEGF-induced, Stat3+/+ (middle) and VEGF-induced, Stat3−/− (right) zebrafish. Scale bars: 50 μm. B) Analysis of vascular permeability upon VEGF stimulation in WT Stat3+/+ (n=30) and KO Stat3−/− (n=9) zebrafish.
of therapies to better combat therapy-refractory lung cancer progression (Oncogene, 2022).
Revealing novel molecular mechanisms of lung cancer growth
A better understanding of the molecular
mechanisms that control NSCLC progression is necessary to develop new therapies. We recently demonstrated that a protein called IKKα drives NSCLC growth through activation of oncogenic signaling via DARPP-32-mediated inhibition of protein phosphatase 1 activity (manuscript in review, npj Precision Oncology).
Identifying new regulators of prostate cancer progression
Our research seeks to understand how overexpression of DARPP-32 in prostate tumors contributes to cancer progression in order to develop new innovative therapeutic strategies to improve tumor control and extend the lives of prostate cancer patients. This work is supported by a generous internal Prostate Cancer Research Award.
Vascular permeability in cardiovascular disease, cancer, and COVID-19-associated acute lung injury
Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular permeability is induced by a protein called VEGF (i.e. vascular endothelial growth factor). Given the prominent role of VEGF in promoting pathologies associated with cancer,
stroke, cardiovascular disease, retinal conditions, and COVID-19-associated acute lung injury, inhibiting vascular permeability mediated by VEGF and inflammation
is an important therapeutic pursuit. We have shown that VEGF mediates vascular permeability through a protein called STAT3 (Figure 1), and thus, targeting the STAT3 signaling cascade represents a promising strategy to reduce pathological effects of permeability during cancer, cardiovascular disease, and lung injury. Dr. Li
Wang, a talented postdoctoral fellow in our group, has coordinated this research. We have used a variety of in vitro and in vivo models to understand the molecular basis of STAT3-regulated permeability (Disease Models & Mechanisms, 2021). We have also recently identified phospholipase C β2 as a key positive regulator of VEGF-induced vascular permeability (Arteriosclerosis, Thrombosis, & Vascular Biology, 2022).
Lab research activities:
https://www.hi.umn.edu/research/ research-sections/cancer-biology/
ORCID iD: https://orcid.org/0000- 0003-3948-4244
Recent Publications:
• Phoenix, K. N., Yue, Z., Yue, L., Cronin, C. G., Liang, B. T., Hoeppner, L. H., & Claffey, K. P. (2022). PLCβ2 Promotes VEGF-Induced Vascular Permeability. Arterioscler Thromb Vasc Biol, 42(10), 1229-1241.
• Alam, S. K., Zhang, Y., Wang, L., Zhu, Z., Hernandez, C. E., Zhou, Y., Yang, N., Lei, J., Chen, X., Zeng, L., Klein, M. A., & Hoeppner, L. H. (2022). DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma. Oncogene, 41(1), 83-98.
• Hartono, S. P., Bedell, V. M., Alam, S. K., O’Gorman, M., Serres, M., Hall, S. R., Pal, K., Kudgus, R. A., Mukherjee, P., Seelig, D. M., Meves, A., Mukhopadhyay, D., Ekker, S. C., & Hoeppner, L. H. (2022). Vascular Endothelial Growth Factor as an Immediate-Early Activator of Ultraviolet-Induced Skin Injury. Mayo Clin Proc, 97(1), 154-164.
• Wang, L., Astone, M., Alam, S. K., Zhu, Z., Pei, W., Frank, D. A., Burgess, S. M., & Hoeppner, L. H. (2021). Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability. Dis Model Mech, 14(11), dmm049029.
• Alam, S. K., Wang, L., Ren, Y., Hernandez, C. E., Kosari, F., Roden, A. C., Yang, R., & Hoeppner, L. H. (2020). ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation. Br J Cancer, 123(5), 819-832.