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Principal Investigator: Shuk-Mei Ho
Organization: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
Fiscal Year: 2024
Funding agency: Veterans Affairs
According to the United States (US) Census Bureau, the number of veterans in the US in 2018 was around 19.9
million. Nine out of 10 were males, and 33% were between 50-69 years old, an age group that is at the highest
risk for prostate cancer (PCa). The VA Central Cancer Registry consistently shows that PCa is the most
frequently diagnosed cancers among male veterans, accounting for >30% of the approximately 50,000 cancer
diagnoses. There is growing concern that environmental and/or occupational exposure to metal ions during
deployment and post-deployment increases PCa risk in veterans. The International Agency for Cancer Research
classified inorganic arsenic (iAs) as a carcinogen, while lead (Pb) is a potential carcinogen in humans. Pb
exposure is a known hazard of military service, while data for iAs exposure is less well-established. Further,
wide-spread exposure to these metal ions in veterans could be mediated through inhalation, ingestion, and
dermal adsorption of toxic smoke from burning oil fields and waste disposal burn-pits. iAs and/or Pb exposure
have been considered potential risk factors for PCa, but the underlying mechanism is largely undefined. In a
small clinical study, we found that iAs and Pb levels were significantly higher in the urine of PCa patients
compared to controls. Using our new 2-hit animal model, we found that exposure to iAs or Pb increased (1) PCa
risk in vivo and (2) the ability of prostate epithelial stem-like cells (PrESLCs) isolated from treated animals to
form colonies in soft agar, a hallmark of cellular transformation. In this animal model, a 1-month metal treatment
followed by chemical carcinogen treatment significantly increased the incidence of PCa and pre-cancerous
lesions in iAs-treated mice, with similar trends in Pb-treated animals. Importantly, single-cell RNAseq analyses
revealed that Pb was associated with the expansion of a subpopulation of PrESLCs with epithelial lineage
markers into stroma-like oncogenic cells, while iAs was associated with the emergence of a rare, unique
subpopulation of oncogenic PrESLCs similar to “cancer” stem cells. This proposal will test the hypothesis that
iAs and/or Pb dysregulate specific, and likely different, signaling pathways in subpopulations of
PrESLCs to initiate or increase the risk of carcinogenesis in the prostate. This is an untested hypothesis
in the field of prostate carcinogenesis and in military veterans’ health. Two Aims are proposed. Aim 1: Determine
the carcinogenic potential of metal treated PrESLCs in vivo using a renal grafting model of PCa formation. We
will evaluate the effects of metals on the formation of PCa in vivo in immune-deficient host mice, either with or
without chemical induction of PCa. Aim 2: Characterize stem-like cells with metal-specific transcriptomic
signatures. We will use single-cell RNAseq and visualization informatics to identify the unique gene signatures
that characterize rare subpopulations of metal-induced cancer stem cells within the PrESLC population. We aim
to apply these gene signatures to enrich rare subpopulations by FACS and evaluate their carcinogenic potential.
We will also leverage The Cancer Genome Atlas PCa data and other online databases to enable accurate
classification of major, rare, and heterogeneous subtypes of PrESLCs to gain insights into metal carcinogenesis.
Findings from the proposed work may address questions related to occupational and post-deployment exposure
and expand our knowledge of stem cell biology. Successful completion of these studies may lead to the
development of new PCa prevention and therapeutic strategies. Plans to reduce unnecessary exposure to those
metal ions can be justified and implemented as effective strategies for PCa prevention. Drugs targeting specific
subpopulations of stem cells may be used as therapeutic options to prevent early PCa development and slow
progression. When applied to veterans, the results of this study may save lives, improve health, and decrease
disabilities in this community and beyond.
Terms: <21+ years old><Accounting><Address><Adsorption><Adult><Adult Human><Afghanistan><Agar><Androgen Suppression><Animal Model><Animal Models and Related Studies><Animals><Anniversary><Armed Forces Personnel><Aromatic Polycyclic Hydrocarbons><Arsenic><Asthma in Children><Award><Barker Hypothesis><Biological Markers><Body Fluids><CMKRL2><Canada><Cancer Causing Agents><Cancer Induction><Cancer Patient><Cancer Research Programs><Cancer Research Project><Cancers><Carcinogens><Cell Body><Cell Death><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cellular Transformation><Censuses><Chemicals><Chemokine Receptor-Like 2><Childhood Asthma><Chronic Disease><Chronic Illness><Classification><Clinical Research><Clinical Study><Communities><Congresses><Cord Blood><Data><Data Bases><Databases><Department of Defense><Dermal><Development><Diagnostic><Disease><Disorder><Disparities><Disparity><Drug 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population><stem cells><stem-like cell><summit><symposia><symposium><toxic exposure><toxicant><transcriptomics><translation><trend><tumor suppressor><understudied cancer><urinary><urologic><urological><veteran population><waste disposal><workplace exposure>