Tumor Biology and Microenvironment Theme 2 Accomplishments
The recognition of the seed-soil hypothesis of tumor metastasis underscores the complexity of the evolving vicious cycles of tumor/stroma interactions in tumor progression. Mechanistic studies of tumor invasion and metastasis continue to be the strength of investigators in our program. Using the combination of cutting edge animal models and 3D culture systems, pioneering work by our members helps established a novel proteolysis/signaling network that enable tumor cells to adapt to and eventually overcome the varying microenvironments. The signaling molecules implicated include PDGF-D, PDGDR, RANKL, RANK, PTH, MKP1, HGF, CXCR1, c-kit, AR, maspin and PTEN. The molecules involved in proteolysis include: MT1-MMP, uPA, matriptase and cathepsin K. A few examples are summarized below.
Theme 2 highlight-A proteolysis/signaling network at sites of prostate cancer bone metastasis.
Dr. H-R Kim is a leading expert in the field of PDGF receptor signaling through the PDGF-C and PDGF-D isoforms, both have been shown to be more pertinent PDGFR ligands than PDGF-A or DGF-B in regulating cancer cell biology. Dr. H-R Kim and colleagues showed that prostate cancer cells-derived PDGF-D enhanced prostate tumor growth in mouse bone, phenotypically similar to that observed in human prostate cancer bone metastasis (ref). In this study, they showed the first evidence that PDGF-D acts as a potent inducer of osteoclastogenesis, independent of the RANKL/RANK pathway. Interestingly, PDGF-D, but not PDGF-B, is sensitive to matriptase-mediated cleavage/activation (ref). Taken together, PDGF-D signaling is likely an ideal therapeutic target for its direct involvement in the vicious cycle of tumor/bone interaction.
Cathepsin K (CTSK) is a predominant bone-resorbing enzyme in physiological and pathological bone remodeling. CTSK has been considered an osteoclast-derived enzyme. Recently, Dr. I Podgorski and colleagues mapped out the sources of CTSK in tumor progression, and showed that bone marrow macrophages (BBM), which share common progenitors with osteoclasts and are critical components of bone tumor microenvironment, are the major source of inflammatory factors and proteases including CTSK. Using a CTSK-deficient mouse (KO) model, they showed that BBM-supplied CTSK was involved in CCL-2 and COX-2-driven pathways, both are essential in prostate tumor bone metastasis (ref).
The laboratory of Dr. S Chinni focuses on the biological function and underlying mechanisms of chemokine receptor CXCR4 and its ligand CXCL12 in prostate tumor metastasis and drug resistance (ref). Dr. Chinni showed that common genetic changes such as PTEN loss or the TMPRSS2-EGR gene fusion may promote tumor progression, at least in part, through the upregulation of CXCR4 (ref). CXCR4 can be blocked by AMD3100, which is an FDA approved anti-HIV drug and showed some promise in a clinical trial for treatment of myeloma. Considering the earlier evidence that TMPRSS2-ERG fusion renders ERG expression under the control of androgen receptor, the new results from the Chinni laboratory not only highlight a common need in heterogeneous prostate cancer cells for CXCR4/CXCL12, but also suggest that CXCR4/CXCL12-targeted therapy may be effective in treating prostate cancer.
The strengths of our program in proteolysis and signaling have extended into a number of exciting new directions. For example, Dr. S Todi made a unique contribution to the field of protein ubiquitination/deubiquitination by the development of a Drosophila model. To date, 41 new Drosophila deubiquitinases have been uncovered, most of which have human orthologues and are linked to diverse functions ranging from development, motility, to longevity (ref). In the study of deubiquitinating enzyme JosD1, Dr. Todi and colleagues discovered that the dynamics of ubiquitination and deubiquitination underlies the cell membrane dynamics and endocytosis (ref). In another study, Dr. Todi and colleagues identified a novel mechanism by which ubiquitin-conjugating enzyme Ube2w ubuquitinates lysine-less but not N-terminally blocked substrates (ref).
A unique feature of the novel collagen receptor discoidin domain receptor (DDRs) is their prolonged activated state, which may sustain the tumor-promoting signal transduction. The laboratory of Dr. Fridman showed that membrane-type metalloproteinases (MT1-MMPs), but not secreted MMPs, directly cleave the ectodomain of DDR1 and inhibit DDR1 activation (ref). The EJXM region of DDR1 and DDR2 is specifically targeted by the protealytic cleavage. This study raises a concern about the broad-spectrum MT-MMP-targeted therapy, i.e., it may help preserve DDR-mediated aggressive tumor phenotype (Figure 5). Further Mutagenesis analysis by the Fridman Lab showed that N211DS glycosylation enhances receptor dimerization and results in ligand-independent receptor autophosphorylation. Given that DDRs have been implicated in the progression of breast cancer and lung cancer, these studies highlight a new structural feature that regulates DDR1 activation (Ref), and may be the basis for the development of novel DDR1 inhibitors.
The first characterization of the biochemical and biological activities of a novel collagen receptor DDR.
Advances in the collaborative research in the area of proteolysis/signaling network in the regulation of prostate cancer bone metastasis led to an investigator-initiated clinical study at KCI to examine whether the collection of these molecules may serve as a specific signature for the diagnosis and prognosis of prostate cancer bone metastasis. In the meantime, Dr. Vaishampayan has been active in conducting multi-institutional clinical studies in several types of urological cancer. Currently, docetaxel-refractory disease within metastatic castrate-resistant prostate cancer presents a serious therapeutic challenge. Platinum-based therapy has demonstrated clinical efficacy in docetaxel refractory patients. Based on the preclinical evidence, Dr. Vaishampayan and colleagues conducted a Phase II clinical trial of bevacizumab and satraplatin in docetaxel-pretreated metastatic castrate-resistant prostate cancer. The primary goal of median TTP-exceeding five months was achieved. Ideally, selection of a patient population likely to benefit from platinum-based therapy would help guide the choice of agent and improve the efficacy of the chemotherapy. Interestingly, ERCC1 TT/CT genotype demonstrated a significantly higher likelihood of benefit with CC genotype in this study (ref).