Tumor Biology and Microenvironment Theme 1 Accomplishments
Tumor cell phenotypical plasticity underlies tumor metastatic potential and drug resistance. It is important to understand its molecular mechanisms in order to develop curative
Examples of novel mechanisms uncovered by TBM members as regulators of the phenotypical plasticity of tumor cells or stem cells.
cancer therapy. TBM members identified and characterized several novel molecular mechanisms governing the plastic EMT or MET process. As highlighted in the image to the right, galectin-3, the pair of tissue type inhibitor of matrix metalloproteinase 1 (TIMP1) and CD63 and platelet-derived growth factor C (PDGF-C) promote EMT, whereas tumor suppressor maspin and nutraceutical B-DIM can induce MET. It is a consensus that tumor cell plasticity and stem cell biology share key molecular pathways (e.g., Wnt/Notch pathway) and the control of one-carbon metabolism by threonine catabolism. Dr. R Valdivia-Fernandez showed that the activity of Notch receptor depends on Rumi. Recent studies of Dr. J Wang showed that threonine catabolism can play a powerful role in the control of the self-renewal of mouse embryonic stem cells. Dr. R Fernandez-Valdivia who discovered Rumi, the sole protein O-glycosyltransferase that activates Notch receptor, plays a key role in mammary gland development and carcinogenesis. Dr. J Granneman collaborated with colleagues in other institutions and resolved the structure of stem-cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5. This major advancement is expected to aid the development of comprehensive Wnt-targeted therapy.
Dr. H-R Kim and colleagues showed that tissue inhibitor of matrix metalloproteinase type 1 (TIMP1) that is frequently overexpressed in several types of human cancers and serves as a prognostic marker, promotes EMT. Overexpression of TIMP1 in normal immortalized mammary epithelial cells MCF-10A, or Madin-Darby canine kidney (MDCK) cells, prevents cell polarization and acinar-like structure formation in 3 dimensional (3D) Matrigel. Concomitantly, TIMP-1 induces expression of the developmental EMT transcription factors such as SLUG, TWIST, ZEB1 and ZEB2, leading to down regulation of epithelial marker and up regulation of mesenchymal markers. Importantly, TIMP-1′s ability to induce the EMT-like process is independent of its MMP-inhibitory domain. This concept represents a paradigm shift in the current view of TIMP-1/MT1-MMP interactions and functions during cancer development/progression.
Maspin, a 42 KDa protein identified as a tumor suppressor gene in 1994, is a member of the serine protease inhibitor (SERPIN) superfamily but acts only as a serpin-like molecule to inhibit serine protease-like protein histone deacetylase 1 (HDAC1), which is a predominant nuclear HDAC and upregulated in many types of cancer. In the progression of prostate cancer and lung adenocarcinoma, maspin is first translated from the nucleus to the cytoplasm, and then down-regulated all together at the step of tumor invasion. This evidence demonstrates an inverse correlation between maspin and EMT. Consistently, Dr. S Sheng and colleagues showed that expression in prostate cancer cell line DU145 induced MET both in 3D collagen I culture and as an intraosseus xenograft tumor in vivo, by reprogramming the gene expression. Recently, the Sheng group identified a specific cis-element in maspin that controls maspin trafficking between the nucleus and cytoplasma. This newly discovered novel structural-functional relationship of maspin is likely to guide the development of more biologically competent HDAC inhibitors for chemotherapy.
Towards therapeutic development, Dr. JJ Wang developed a novel (proprietary) QQ protein delivery technology. In collaboration with Dr. G Wu (MT), Dr. Wang received an NIH/NCI MPI-R01 to study the therapeutic potential of tumor-targeted QQ delivery of Sox2/Oct4/Nanog in treating metastatic breast cancer. Dr. K Reddy showed that the combination of cisplatin and TRAIL is particularly effective in eliminating the stem-like population for triple negative breast cancer cells both in vitro and in vivo.
To develop novel molecular markers for cancer diagnosis and prognosis, Dr. A Raz and colleagues recently developed a sensitive ELISA method to detect Galectin 3 in serum, and showed that galectin-3 levels in the sera of patients with metastatic PCa were uniformly higher as compared to the non-cancer patient controls. The data suggest that galectin-3 serum level may be a useful serum marker for the diagnosis or recurrence of prostate cancer. Dr. A Raz and colleagues also showed that the combination of PSA/PTEN/c-Able/Galactin-3 may serve as a better new prognostic signature for prostate cancer. In the study by Dr. R Ali-Fehmi and colleagues with a tissue microarray of 261 cases of invasive breast cancer, the expression of zeste homolog 2 (EZH2) is strongly associated with triple negative breast cancer, higher histologic grade, and poorer overall survival. EZH2 promotes the growth of triple negative breast cancer cells in vitro and in vivo (ref). This group also showed that EZH2 is targeted by miRNA101 in pancreatic ductal adenocarcinoma, and can inhibit epithelial-to-mesenchymal transition (EMT). Treatment of pancreatic cancer with miRNA101 significantly attenuated tumor growth in vivo (ref).