Tumor Microenvironment and Metastasis
Ningling Kang, Ph.D.
“Liver metastasis remains a principal cause of patient death
despite significant advances in the treatment of cancer and
this metastatic liver disease.”
Dr. Ningling Kang
The liver is a preferred organ for cancer metastasis, and liver metastasis remains a principal cause of patient death. Our research program is focused on bidirectional interactions between cancer cells and the liver.s microenvironment that critically regulate the development of liver metastasis.
We specifically are interested in the interactions between cancer cells and hepatic stellate cells (HSCs), which are liver resident cells. We study how cancer cells induce activation of hepatic stellate cells into cancer-promoting fibroblasts and how activated HSC/fibroblasts promote implantation and proliferation of cancer cells in the liver.
We have identified three critical mechanisms that control TGF-.-mediated activation of HSCs, which might present important therapeutic targets to inhibit HSC activation. 1) We found that vasodilator-stimulated phosphoprotein (VASP) promotes HSC activation by regulating the targeting of TGF-. receptors to the plasma membrane. VASP forms a protein complex with Rab11, a key molecule regulating recycling of TGF- . receptors, and VASP is required for Rab11-dependent recycling of T.RII to the plasma membrane. VASP of HSCs promotes cancer cell proliferation and growth in a cancer/HSC coculture and coimplantation mouse model. In patients, high VASP expression levels in hepatocellular carcinoma correlate with poor survival of patients. These data led us to an extended study focusing on the role of VASP in cancer cells. We found that VASP of cancer cells is required for adhesion and proliferation of cancer cells disseminated in the liver, requisite for the development and progression of liver metastasis. Together, these data highlight VASP as a therapeutic target for liver metastasis. 2) PDGF receptor alpha (PDGFR.) promotes HSC activation via regulating TGF-. receptors. HSCs express both PDGFR. and PDGFR. receptors. PDGFR. but not PDGFR., however, is required for TGF- .-mediated activation of HSCs. PDGFR. forms a protein complex with TGF-. receptors, which is required for internalization of TGF-. receptors and TGF-. downstream signaling. PDGFR. of HSCs promotes colorectal cancer cell proliferation and migration in vitro, and it is upregulated when cancer cells invade the liver in a liver metastasis mouse model and colorectal cancer patients. Thus, PDGFR. can cross-talk with TGF-. receptors to promote activation of HSCs. 3) One ongoing study is focused on the role of E1A-binding protein p300 (p300) in HSC activation; p300 is an acetyltransferase with a poorly defined role in HSCs and amenable to inhibition by small molecule. Our preliminary data demonstrate that p300 facilitates transcription of TGF-.-induced target genes in the nucleus, thereby promoting HSC activation. Thus, p300 presents another important target to inhibit HSC activation and the prometastatic liver microenvironment.
Presentations (7/1/2014 – 6/30/2015)
Oral Presentation at The Liver Meeting, AASLD, Nov. 7-11, 2014, Boston. VASP
mediates plasma membrane targeting of TGF-beta receptor II and myofibroblastic
activation of hepatic stellate cells.
Publications (7/1/2014 – 6/30/2015)
1. Tu K, Li J, Verma VK, Liu C, Billadeau DD, Lamprecht G, Xiang X, Guo
L, Dhanasekaran R, Roberts LR, Shah VH, Kang N. Vasodilator-stimulated
phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-
dependent plasma membrane targeting of transforming growth factor beta receptors.
Hepatology. 2015 Jan;61(1):361-74. doi: 10.1002/hep.27251. Epub 2014 Sep 19.
2. Bi Y, Li J, Ji B, Kang N, Yang L, Simonetto DA, Kwon JH, Kamath M, Cao S, Shah V.
Sphingosine 1-phosphate mediates a reciprocal signaling pathway between stellate
cells and cancer cells that promotes pancreatic cancer growth. Am J Pathol. 2014 Oct;
184(10):2791-802. doi: 10.1016/j.ajpath.2014.06.023. Epub 2014 Aug 8.
3. Liu C, Li J, Xiang X, Guo L, Tu K, Liu Q, Shah VH, Kang N. PDGF receptor alpha
promotes TGF-β signaling in hepatic stellate cells via transcriptional and post
transcriptional regulation of TGF-β receptors. Am J Physiol Gastrointest Liver Physiol.
2014 Oct 1;307(7):G749-59. doi: 10.1152/ajpgi.00138.2014. Epub 2014 Aug 28.
4. Kang N, Shah VH and Urrutia R. Membrane-to-Nucleus Signals and Epigenetic
Mechanisms for Myofibroblastic Activation and Desmoplastic Stroma: Potential
Therapeutic Targets for Liver Metastasis? Mol Cancer Res. 2014 Dec 29.
pii: molcanres.0542.2014. [Epub ahead of print].