Page 21 - Annual Report 2020

Our laboratory has several projects under three categories: 1- Mechanisms of Ciliary Loss, 2- Consequenc- es of Ciliary Loss, and 3-New therapies and translational studies. We briefly describe below two of them.
Mechanisms of Ciliary Loss
Our long-term goals are to understand the patho- genesis of cholangiocarcinoma (CCA) and develop new therapies for its treatment. Our current overall objective is to explore the importance of cholan- giocyte deciliation, a pathologic process recently discovered by us in the pathogenesis and progres- sion of CCA. We proposed that autophagy, a physi- ological process that degrades organelles, is linked to ciliary disassembly by a mechanism dependent on HDAC6, which is a protein overexpressed in tumor cells and induces the resorption of cilia by regulating ciliary stability and the transport of its components to the cellular degradative compart- ments. We hypothesized that by pharmacological inhibition of HDAC6 and/or autophagy, it is possi- ble to restore the expression of cilia on tumor cells and transform them back to a less aggressive and more normal phenotype.
Figure 1
WT1 Regulatory Axis in Cholangiocarcinoma
The Wilms’ tumor gene (WT1) was recently found as a key regulator of the genetic network of on- cogenic KRAS. It has been shown that WT1 can promote cancer invasion through direct binding to the CDH1 promoter. Furthermore, WT1 was found to promote cancer cell proliferation by upregulating Cyclin D1 and p-pRb expression in vitro and in vivo. As evidence accumulates on different tumor types that overexpress WT1, it is clear that WT1 has a dichotomous role in cancer, and indeed, WT1 has been referred to as a chameleon. The regulation and role of WT1 in cholangiocarcinoma remains unknown, but our data show that the loss of cilia induces WT1 expression. Interestingly, in pan- creatic cancer and cholangiocarcinoma, overexpression of WT1 is seen in 65% to
75% of the cases. We found that normal experimentally deciliated cells have a higher expression of KRAS, MAPK, and WT1 signaling pathways. Therefore, we hypothesized that the presence of cilia normally inhibits the activation of KRAS, WT1 and its downstream signaling thereof (Figure 2). This study is uncovering the relation between primary cilia loss and overexpression of WT1, a novel concept in the pathogenesis of CCA. Therefore, tar- geting WT1 or other related downstream target gene products may have clinical implication in CCA patients.
Figure 2
Publications:
1. Mansini AP, Peixoto E, Jin S, Richard S, Gradilone SA. “The chemosensory function of primary cilia regulates cholangiocyte migration, invasion and tumor growth.” Hepatology 69(4):1582-1598, 2019.
2. Peixoto E, Richard S, Pant K, Biswas A, Gradilone SA. “Primary cilia: their role as a tumor suppressor organelle.” Biochem Pharmacol, Mar 10;175:113906. doi: 10.1016/ j.bcp.2020.113906. Online ahead of print, 2020.
3. Pant K, Peixoto E, Richard S, Gradilone SA. “Role of Histone Deacetylases in Molecular Pathogenesis of Cholangiocarcinoma” Cells 23;9(3):780, 2020.
4. Peixoto E, Jin S, Thelen K, Biswas A, Holtorf S, Richard S, Mansini AP, Morleo M, Carbone F, Pastore N, Franco B, Ballabio A, Gradilone SA. “HDAC6-dependent ciliophagy is involved in ciliary loss and cholangiocarcinoma growth in human cells and murine models” Am J Physiol Gastrointest Liver Physiol. 318(6):G1022-G1033, 2020.
THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 21