Precision Medicine of Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Precision medicine in cancer is multifaceted and our research, following the bench to bedside approach, has led to significant discoveries that will advance the diagnostic and prognostic utilization of biomarkers and elucidate the role and mechanism the microbiome plays in lung carcinogenesis. In addition, researching health disparity remains a focus (Graff, M. et al., Am J Hum Genet. 108: 564-582, 2021; Jiang M. et al. Lung Cancer 152: 58-65, 2021) that build on the laboratory's legacy of having been the first to conduct GWAS in the US population of African heritage (Zanetti KA. et al., Lung Cancer 98: 33-42, 2016). Cancer Microbiome: A recent study of microbiota composition revealed an abundance of bacteria in several cancer types once thought to be sterile (Greathouse KL. et al., Cancer Cell 38: 158-160, 2020). We have discovered Acidovorax spp associated with TP53 mutations and smoking in both adenocarcinoma and squamous cell carcinoma. Using a mouse model of lung cancer, we show Acidovorax spp is a contributor, not a passenger, of lung carcinogenesis, via activation of proinflammatory lung neutrophils. Our data showed that mice exposed to A. temperans (Acidovorax temperans) had significantly larger tumor burden and more abundant lung lesions compared to PBS-instilled (sham) control mice. A. temperans instillation is deleterious to survival and repeated exposure accelerates lung tumor development in tumor-bearing mice, thus, A. temperans has a functional role in lung cancer development. Whole tissue RNA sequencing (RNAseq) comparing differential gene expression in A. temperans-instilled mice and sham controls showed a strong inflammatory response to A. temperans through MyD88-dependent signaling, a pathway essential to launch innate and adaptive immunity, and contributes to cancer progression. In collaboration with Romina Goldszmid, we investigated the changes in the tumor immune microenvironment upon instillations with A. temperans. Our fluorescence activated cell sorting (FACS) analysis results showed an increase of CD45+ve immune populations in the lungs of A. temperans-instilled mice driven by neutrophils, CD4+ve, CD8+ve, double negative (DN) T-cells as well as an increase in gamma-delta T cells. Overall, our results indicate that A. temperans increases infiltration of proinflammatory cells, which sustained over time, promote lung adenocarcinoma development. Neutrophil recruitment is exacerbated in the lungs of KPC mice upon challenge with A. temperans. The phenotype of the infiltrated neutrophils in A. temperans -instilled mice have increased frequency of CD44lowICAM1highSiglecF+PDL1+ neutrophils, previously characterized as long-lived, mature pro-tumorigenic tumor-associated neutrophils, important for lung tumor progression in KPC mice. RNAseq showed higher signature scores for activated and mature neutrophils in A. temperans-challenged mice. Bacterial exposure is likely the reason for neutrophil maturation, so we compared scores for a previously reported neutrophil signature of pathogenic Escherichia coli (E. coli) infection and found that A. temperans-instilled mice had higher signature scores for neutrophil maturation due to bacterial infection. Neutrophils are the dominant immune cell population in the tumor microenvironment of lung cancer patients and evidence shows that an increased ratio of circulating neutrophils to leukocytes is associated with poor prognosis, and worse response to therapy, including immunotherapy. Next is to develop a therapeutic mouse model and to validate the role of neutrophils in mediating A. temperans-induced lung tumorigenesis. Cancer Metabolome: Correlation of identified metabolites with specific cancers created biomarker profiles that can be utilized for non-invasion diagnostic and prognostic evaluation of many types of human cancer. Liquid biopsy of urine, serum and plasma are used to measure four biomarkers (creatine riboside (CR), N-acetylneuminic acid (NANA), cortisol sulfate (CS), and 27alpha-nor-5beta-cholestane-3aplpha, 7alpha, 12alpha 24alpha, 25alpha Pentol glucuronide (NCPG) of lung cancer by mass spectrometry (Haznadar, M. et al., Cancer Epidemiol. Biomarker Prev. 25:978-86, 2016). CR paired with other identified urinary metabolite biomarkers such as (NANA) improve diagnostic capability and reliability. We have shown that creatine riboside (CR) is a cancer cell-derived metabolite that at high levels, is associated with mitochondrial urea cycle dysregulation and it an indicator of poor prognosis for cancer patients(Parker, A. et al., JNCI 132(14),2022). These foundational studies validated the use of urinary metabolite screening leading to further investigation into biomarker association with human cancer. (Patel, DP. et al. J Pharm Biomed Anal. 191: 113596, 2020) And as mentioned in the 2020 and 2021 annual report, urinary metabolite biomarker profiling could offer diagnostic and prognostic evaluation of intrahepatic cholangiocarcinoma (ICC). Employing UPLC-MS/MS, four metabolites, for the quantitation of metabolites CR, N-acetylneuraminic acid (NANA), cortisol sulfate, and a glucuronide fragmented ion designated as 561+, are significantly increased in HCC and ICC and are robust at classifying ICC in combination with a clinically utilized marker CA19-9. NCI-MD cohort were studied and observations verified by the TIGER-LC cohort. We determined properties that are significant for a biomarker to its use in CLIA based assays of biomarkers in liquid biopsy.