Chaoyang Sun

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor–stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

BACKGROUND: Although research on the effects of comorbidities on coronavirus disease 2019 (COVID-19) patients is increasing, the risk of cancer history has not been evaluated for the mortality of patients with COVID-19. METHODS: In this retrospective study, we included 3232 patients with pathogen-confirmed COVID-19 who were hospitalized between January 18th and March 27th, 2020, at Tongji Hospital in Wuhan, China. Propensity score matching was used to minimize selection bias. RESULTS: In total, 2665 patients with complete clinical outcomes were analyzed. The impacts of age, sex, and comorbidities were evaluated separately using binary logistic regression analysis. The results showed that age, sex, and cancer history are independent risk factors for mortality in hospitalized COVID-19 patients. COVID-19 patients with cancer exhibited a significant increase in mortality rate (29.4% vs. 10.2%, P < 0.0001). Furthermore, the clinical outcomes of patients with hematological malignancies were worse, with a mortality rate twice that of patients with solid tumors (50% vs. 26.1%). Importantly, cancer patients with complications had a significantly higher risk of poor outcomes. One hundred nine cancer patients were matched to noncancer controls in a 1:3 ratio by propensity score matching. After propensity score matching, the cancer patients still had a higher risk of mortality than the matched noncancer patients (odds ratio (OR) 2.98, 95% confidence interval (95% CI) 1.76-5.06). Additionally, elevations in ferritin, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, procalcitonin, prothrombin time, interleukin-2 (IL-2) receptor, and interleukin-6 (IL-6) were observed in cancer patients. CONCLUSIONS: We evaluated prognostic factors with epidemiological analysis and highlighted a higher risk of mortality for cancer patients with COVID-19. Importantly, cancer history was the only independent risk factor for COVID-19 among common comorbidities, while other comorbidities may act through other factors. Moreover, several laboratory parameters were significantly different between cancer patients and matched noncancer patients, which may indicate specific immune and inflammatory reactions in COVID-19 patients with cancer.

BACKGROUND: Expression of BRCA1 is commonly decreased in sporadic ovarian cancer, and this is associated with platinum sensitivity and favorable prognosis. However, multiple mechanisms underlying low BRCA1 expression are not fully understood. METHODS: A bioinformatics-driven microRNA (miR) library screening was used to identify miRs that regulate BRCA1 expression. The effects of miR-9 on cisplatin (cDDP) and PARP inhibitor sensitivity were measured in ovarian cancer cells and C13* xenograft mice (n = 6 per group). The roles of miR-9 on prognosis were assessed in a cohort of ovarian cancer patients (n = 113) with Kaplan-Meier and Cox proportional hazards analyses. All statistical tests were two-sided. RESULTS: Reverse miR library screening revealed that miR-9 reduced the normalized luciferase activity to 60.3% (95% confidence interval [CI] = 52.0% to 68.5%; P < .001). miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells. Treatment with miR-9 agomiR sensitized BRCA1-proficient C13* xenograft tumors to cisplatin and AG014699. In serous ovarian cancer, higher levels of miR-9 were inversely correlated with BRCA1 expression (Spearman rank correlation: R (2) = 0.379; P = .003). Patients with higher levels of miR-9 had better chemotherapy response, platinum sensitivity, and longer progression-free survival (PFS) (high vs low miR-9 expression: median PFS = 26.4 months, 95% CI = 13.8 to 39.0 months vs median PFS = 15.4 months, 95% CI = 6.8 to 23.9 months, P = .01). CONCLUSIONS: miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer. miR-9 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage and may impact ovarian cancer therapy.