Zeneng Wang

Disruption of the Gut Microbiota Confers Cisplatin Resistance in Epithelial Ovarian Cancer

Abstract Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity. Significance: Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer. See related commentary by Hawkins and Nephew, p. 4511

Associations of serum trimethylamine N‐oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort

AbstractBackgroundDietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N‐oxide (TMAO) and its precursors, choline, L‐carnitine, and betaine.MethodsProspective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L‐carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori–selected dietary exposures with the four metabolites were also investigated.ResultsTMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] = 1.90 [CI, 1.24–2.92; p = .003] and 1.26 [1.17–1.36; p < .0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI] = 0.77 [0.76–0.79; p < .001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho = 0.10; p = .0003).ConclusionsSerum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Leveraging dysregulated tumor metabolism for targeting anticancer bacteria

Widespread application of bacterial-based cancer therapy is limited because of the need to increase therapeutic bacteria specificity to the tumor to improve treatment safety and efficacy. Here, we harness the altered tumor metabolism and specifically elevated kynurenine accumulation to target engineered bacteria to the cancer site. We cloned and leveraged kynurenine-responsive transcriptional regulator (KynR) with its cognate promoter in Escherichia coli . Optimizing KynR expression coupled with overexpressing kynurenine transporter and amplifying the response through plasmid copy number–based signal amplification enabled the response to kynurenine at the low micromolar levels. Knocking out genes essential for cell wall synthesis and supplying these genes via kynurenine-controlled circuits allowed tuning Salmonella enterica growth in response to kynurenine. Our kynurenine-controlled S. enterica (hereafter named AD95+) showed superior tumor specificity in breast and ovarian cancer murine models compared to S. enterica VNP20009, one of the best characterized tumor-specific strains. Last, AD95+ showed anticancer properties compared to vehicle controls, demonstrating the potential as an anticancer therapeutic.