Program Leader, Prostate Cancer Research
Our objective is to define how integrin interactions within the tumor microenvironment impact prostate cancer development, hormonal resistance, and metastasis. Our approach is to understand the normal biology of the prostate gland and its microenvironment, as well as the bone environment, to inform on the mechanisms by which tumor cells remodel and use that environment to develop, acquire hormonal resistance, and metastasize. Our research is focused in three primary areas: 1) developing in vitro and in vivo models that recapitulate human disease based on clinical pathology, 2) identifying signal transduction pathway components that could serve as both clinical markers and therapeutic targets, and 3) defining the genetic/epigenetic programming involved in prostate cancer development.
- Prostate cancer remains the second-leading cancer killer of men due to the inability to cure hormone-resistant metastatic disease. Our laboratory is focused on defining the mechanisms of hormone resistance and metastasis, and we hypothesize that the tumor microenvironment plays a major role.
- We have shown that drugs which initially show promise in laboratory settings fail in clinical trials because the existing models for prostate cancer fail to adequately address the role of the tumor microenvironment. We have developed a rational approach to defining how the tumor microenvironment affects cell survival and drug resistance.
- Many men develop prostate cancer that will not progress to lethal disease, but we lack the ability to predict which tumors will progress, resulting in over-diagnosis and unnecessary treatment. We need to identify specific steps in oncogenesis that lead to aggressive disease, and we are addressing the lack of adequate models for primary disease progression by developing new ones.
- Over 80% of prostate cancers metastasize to the bone. We are developing better models to understand both normal bone development and bone/cancer cell interactions.
The AR/α6β1 Integrin Axis
We identified a novel AR survival pathway in androgen-responsive tumors whereby AR in combination with the oncogenic TMPRSS2-Erg fusion protein directly stimulates integrin α6β1 transcription and expression. Engagement of integrin α6β1 by laminin in turn stimulates NF-κB/RelA activation and subsequently increases the transcription of Bcl-xL to promote survival. In hormone-resistant tumors, this same pathway in coordination with HIF1/2 induces a second pathway involving Bnip3. Bnip3 allows for tumor survival under high oxidative stress by targeting damaged mitochondria for degradation through autophagy.
The loss of Pten, which induces PI3K signaling, is common in prostate cancers, yet PI3K inhibitors alone are not effective in patients. When tumor cells are bound to laminin via integrin α6β1, they are resistant to PI3K inhibition. Blocking PI3K in combination with blocking the AR-induced integrin α6β1 pathway re-sensitizes cells to PI3K inhibition. Thus, interaction with the tumor microenvironment through AR/α6β1 is an important mechanism by which prostate tumor cells escape their reliance on PI3K signaling, and disrupting this pathway will be necessary for effectively blocking prostate cancer in vivo.
Differentiation and Oncogenesis
The prostate cancer field is hampered by the lack of cell models that reflect in vivo events. We developed an in vitro differentiation model in which human basal epithelial cells are differentiated into luminal cells as observed in vivo. When we engineer these cells to simultaneously overexpress Myc and TMPRSS2/Erg and inhibit Pten, we generate tumors that mimic human pathology in vivo. Moreover, these tumor cells were unable to differentiate due to loss of the chromatin reader protein ING4. We found that ING4 protein is lost in over 60% of human primary prostate cancers. We are currently determining how ING4 expression regulates chromatin and epigenetic programming to suppress tumorigenesis.
CD82/KAI1 in Bone Development
CD82/KAI1 is encoded by a metastasis suppressor gene whose loss in primary prostate tumors correlates with poor patient prognosis. CD82 is one of 33 tetraspanins whose functions remain enigmatic but are linked to cell adhesion. We generated CD82-null mice to better understand the normal function of CD82. Loss of CD82 in platelets enhanced clot retraction in vitro and reduced bleeding in vivo, which as due in part to an increase in platelet-specific integrin αIIbβ3 expression. We also observe defects in bone osteoclast adhesion and activation, leading to a reduced ability to degrade bone and increased bone density. Mice lacking CD82 also have a decreased ability to clear pathogens due to defects in macrophage signaling.