Metal-induced cell-level changes in prostate epithelium and cancer risk

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1 Data in the Veterans Affairs (VA) Central Cancer Registry showed nearly 50,000 new cases of 2 cancers were diagnosed in the VA system in 2010, and prostate cancer (PCa) is the most frequently 3 diagnosed cancer among male veterans, with ~12,500 cases or 33% of all cancers reported. 4 Inhalation or ingestion of toxic air from incomplete combustion are known to increase exposure 5 to metal ion including lead (Pb) and arsenic (iAs), especially when a great variety of materials 6 were being burnt in burnpit. iAs and/or Pb exposure have been considered as potential risk factors 7 for this cancer, but the underlying mechanism is largely undefined. In a small clinical study, we 8 found that iAs and Pb levels were significantly higher in the urine of PCa patients. Using a new 2- 9 hit animal model we established, exposure to iAs or Pb was showed to increase (1) PCa risk in 10 vivo, and (2) the ability of prostate epithelial stem-like cells (PrESLCs) isolated from treated 11 animals to form colonies in soft agar, a hallmark of cellular transformation. In this animal model, 12 a 1-month metal treatment followed by chemical carcinogen treatment, resulted in significant 13 increases in PCa incidence and pre-cancerous lesions in iAs-treated animal and trends of increases 14 in Pb-treated animals. Importantly, single-cell RNAseq analyses revealed that Pb was associated 15 with the expansion of a subpopulation of PrESLCs with epithelial lineage markers into stroma- 16 like oncogenic cells, while iAs was associated with the emergence of a rare, unique subpopulation 17 of oncogenic PrESLCs similar to “cancer” stem cells. This application will test the hypothesis that 18 iAs and/or Pb dysregulate specific, and likely different, signaling pathways in subpopulations of 19 prostate epithelial stem-like cells (PrESLCs) to initiate or increase the risk of carcinogenesis in the 20 gland. This is an untested hypothesis in the field of prostate carcinogenesis and in military veterans’ 21 health. Two Aims were proposed: 1) Determine the carcinogenic potential of metal-treated prostate 22 epithelial stem-like cells (PrESLCs) in vivo using a renal grafting model of PCa formation assay. 23 We will evaluate the effects of metals on to form PCa in vivo in immune-deficient host mice, either 24 with or without chemical induction of PCa; and 2) Characterize stem-like cells with metal-specific 25 transcriptomic signatures. We will use single-cell RNA sequencing and visualization informatics 26 to identify the unique gene signatures that characterize rare subpopulations of metal-induced 27 cancer stem cells within the PrESLCs population. We aim to apply these gene signatures to enrich 28 rare subpopulations by FACS and evaluate their carcinogenic potential. We will also leverage The 29 Cancer Genome Atlas PCa data and other online databases to enable accurate classification of 30 major, rare, and heterogeneous subtypes of PrESLCs to gain insights in metal carcinogenesis. 31 Findings from the proposed work may address questions related to occupational and post- 32 deployment exposure and expand our knowledge on stem cell biology. Potential Impact on 33 Veterans Health Care: Successful completion of these studies can potentially lead to the 34 development of new PCa prevention and therapeutic strategies. Plans to reduce unnecessary 35 exposure to those metal ions should be implemented as effective strategy for PCa prevention. 36 Drugs targeting to specific subpopulation of stem cells could be used as therapeutic options to 37 prevent early PCa development as well as progression. When applied to veterans, the results of 38 this study may allow saving human lives, improving the health of veterans, and decreasing the 39 number of disabilities in the veteran population.