Unraveling Tumor Microenvironment Heterogeneity in Advanced Prostate Cancer
Abstract
What Makes Prostate Cancer in Each Patient Unique? Prostate cancer is one of the most prevalent (~3,120,176 patients overall) and leading cause of cancer-related death (~29,430 patients) in men. It has been estimated that about 1 in 7 men will be diagnosed with prostate cancer during their lifetime. If the disease remains localized to the site of origin, i.e., the prostate tissue, it is highly treatable and, hence, most men diagnosed with this benign form of prostate cancer do not die; however, some patients progress to an aggressive disease, wherein the cancer spreads to multiple organs and eventually results in death. Although tests are available for identifying prostate cancer, they are typically inaccurate in distinguishing between benign and aggressive disease. Consequently many men either are over-diagnosed and over-treated, resulting in morbidity, financial burden, and psychological stress from multiple biopsies, radical prostate surgery, and prostate radiation treatment, or are inadequately treated and ultimately die prematurely as a result of the disease. Extensive research has suggested that no two tumors are alike, much like how the DNA fingerprint of each person is unique. This tumor characteristic is referred to as tumor heterogeneity, which arises from a combination of patient-intrinsic (e.g., the genetic code of the patient) and environmental factors (e.g., exposure of Veterans to wartime toxins). Such heterogeneity immensely contributes to false interpretation of diagnostic tests and failure of therapy in a significant fraction of prostate cancer patients, although their clinical risk parameters are similar to therapy responders. Therefore, there is an urgent need to understand how prostate cancer becomes more aggressive and the contribution of tumor heterogeneity in these processes to accurately differentiate benign from aggressive disease. The answer to this problem lies within the fundamental unit of tumors, the cells that cause and sustain cancer. The tumor ecosystem is highly complex and comprises diverse types of cells, each of which has a unique molecular (or gene) signature. This scenario is analogous to any socioeconomic ecosystem, wherein the economy of a large country is dependent on the economy of each state, which in turn is defined by the income of unique groups of residents. Variability in the cellular composition of tumors is the underlying reason for tumor heterogeneity. Past technologies could only obtain molecular information as an average of all cells within the tumor and consequently were unable to tackle tumor heterogeneity. Based on our analogy, past technologies could only obtain economic information of the country as a whole, often invoking the question of whether the country’s wealth is equally distributed among all citizens or whether the income from a small fraction of wealthy individuals represent a significantly large proportion of the country’s wealth. To overcome this issue, we developed cutting-edge technologies that obtain molecular signatures from each and every cell of a tumor, termed single-cell analysis. Using this novel tool, we aim to dissect the cellular makeup of prostate tumors, understand the specific cell types within prostate tumors that can make benign tumors become more aggressive, and identify cell-type specific biomarkers that accurately predict advanced prostate cancer. Of particular note, we propose to understand whether exposure to wartime toxins results in a distinct class of prostate cancer in the Veteran population compared to the general population. We also propose to compile all of the identified cell types as a prostate cancer “cell atlas,” which will serve as a valuable resource for researchers interrogating prostate cancer biology and help clinicians improve patient prognostication. The aims of this proposal specifically address two Prostate Cancer Research Program Overarching Challenges: “Reduce lethal prostate cancer in Af
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910424
Entities
People
- Sethuramasundaram Pitchiaya
Organizations
- United States Army
- University of Michigan