Prostate cancer is lethal when it metastasizes to the liver. We have identified for the first time that a steatotic hepatitis (fatty liver) is significantly more receptive to prostate cancer cells than a normal healthy liver. The Veteran population is predisposed to PCa liver metastasis as they have the multiple risk factors for fatty liver. In the course of this proposal our objective is to determine the mechanism of this interesting metastatic phenomena. We have demonstrated that the fatty liver and the primary prostate cancer microenvironment have multiple lines of similarity, including neuroendocrine differentiation of the epithelia, tenascin C matrix expression, and endoglin expression in the tumor stromal cells. We have reported that TGF- signaling in the tumor microenvironment in the primary tumor site or the secondary metastatic site mediates paracrine signaling dictate the expansion and therapeutic resistance of the associated cancer epithelia. The endoglin receptor is a member of the TGF- receptor family that is critical for the switching from the downstream Smad2/3 to the Smad1/5 signaling. This signaling switch can be the determinant for TGF- going from an anti- tumorigenic role to that of a pro-tumorigenic role. Preliminary data support the induction of fatty acid oxidation in the primary tumor and hepatocytes downstream of endoglin as a determinant of tumor epithelial expansion at both primary tumor and metastatic site. In turn, we found that fatty acid metabolism can induce endoglin expression. We will specifically test the hypothesis that, elevated CD105-fatty acid oxidation axis in the PCa microenvironment is supportive of its expansion in the primary and liver metastatic site through the following aims:
Aim. 1. Define the role of CD105 and fatty acid oxidation plays in PCa-associated fibroblasts to support PCa expansion.
Aim. 2. Define the role of CD105 and fatty acid oxidation plays in hepatocytes to support PCa expansion. We will interrogate both stromal and epithelial contributions to the generation and maintenance of a lethal PCa phenotype in the liver. We will use in vivo tissue recombination and patient derived xenograft systems to study the interactions of altered cancer-associated fibroblasts and cancer cells. We will for the first time evaluate endoglin antagonism as a means of limiting PCa liver metastasis. Our studies will leverage access to human tissues from the well-annotated VA Hospital System. Understanding a mechanism for why the fatty liver microenvironment supports PCa tumors and determining how the PCa adapts to the metastatic microenvironment are the goals of this project.
Prostate cancer is the most common cancer diagnosis after cutaneous cancers in the VA population and the second most common cause of cancer death in the approximately 40,000 cases reported in the Veterans Affairs Central Cancer Registry annually. The disproportionate number of deaths from the disease in the Veteran population can be attributed in part due to its metastasis to the liver. Although not the most frequent site for metastasis, the mortality from liver metastasis is the greater than any other site of metastasis. A consequence of alcohol consumption, obesity, diabetes, and smoking is fatty liver disease. These risk factors for fatty liver disease are significantly greater in the Veteran population. We have shown for the first time that prostate cancer metastasis to the fatty liver is dramatically greater than its healthy counterpart. We hypothesize that the primary tumor microenvironment mimics fatty liver microenvironment and endoglin signaling contribute to a permissive niche for metastasis, to support the preclinical trial for an endoglin antagonist proposed.
|Rohena-Rivera, Krizia; Bhowmick, Neil A (2018) Notch inhibitor screening reveals an unexpected HES1 heterodimer. J Biol Chem 293:8295-8296|
|Madhav, Anisha; Andres, Allen; Duong, Frank et al. (2018) Antagonizing CD105 enhances radiation sensitivity in prostate cancer. Oncogene 37:4385-4397|
|Smith, Bethany; Agarwal, Priyanka; Bhowmick, Neil A (2017) MicroRNA applications for prostate, ovarian and breast cancer in the era of precision medicine. Endocr Relat Cancer 24:R157-R172|
|Tripathi, Manisha; Nandana, Srinivas; Billet, Sandrine et al. (2017) Modulation of cabozantinib efficacy by the prostate tumor microenvironment. Oncotarget 8:87891-87902|
|Haldar, Subhash; Dru, Christopher; Mishra, Rajeev et al. (2016) Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. Sci Rep 6:39257|