Biology subjects

Alali, Z.

Publications and source records attributed to Alali, Z..

3 recordsLinked to original sources

bioRxiv2021

A Novel Non-Invasive Epithelial Ovarian Cancer Mouse Model Of Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

BackgroundHyperthermic intraperitoneal chemotherapy (HIPEC) in combination with interval cytoreductive surgery increases the overall survival of epithelial ovarian cancer (EOC) patients with advanced disease. Despite its proven benefits, the mechanism by which HIPEC extends overall survival remains unknown and current strategies to optimize HIPEC are therefore limited. A major challenge is the lack of a robust and streamlined model to investigate the mechanisms underlying HIPEC efficacy. ObjectiveTo introduce a novel murine model that can be used to enhance our understanding of HIPEC therapy. MethodID8-luc, an EOC mouse cell line, is inoculated into immunocompetent C57BL/6J mice intraperitoneally. Once tumor is detected by In Vivo Imaging System (IVIS), cisplatin (5 mg/kg) is injected intraperitoneally and superficial hyperthermia of 40{degrees}C is applied to the animals abdomen and pelvis using an FDA-approved hyperthermia unit (BSD500) for 20 minutes. To validate the model, four treatment conditions were tested: cisplatin and hyperthermia, cisplatin and normothermia, vehicle and hyperthermia, and vehicle and normothermia. Tumor growth was assessed over the course of treatment using IVIS optical spectrum. ResultsTumor growth in mice treated with hyperthermic cisplatin was significantly suppressed compared to mice treated with normothermic cisplatin (p < 0.05). No significant differences in tumor growth were observed in the hyperthermic vehicle and normothermic vehicle groups. ConclusionsWe developed an innovative noninvasive mouse model of HIPEC. Similar to patients with advanced ovarian cancer who are treated with HIPEC at the time of interval cytoreductive surgery, our model demonstrates that hyperthermia enhances the inhibitory effect of cisplatin on intraperitoneal tumor growth. Development of this murine model provides an opportunity to elucidate the mechanisms underlying HIPEC and offer an opportunity to test adjunct treatments in a pre-clinical setting to enhance the utility of HIPEC.

cancer biology↗

bioRxiv2020

Single-Cell Analysis of Hyperthermic Intraperitoneal Chemotherapy Treated Tumors Reveals Distinct Cellular and Molecular Responses

Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a clinical regimen that prolongs overall survival for patients with advanced Epithelial Ovarian Cancer (EOC). However, the mechanism of action of HIPEC remains poorly understood. To provide insights into the rapid changes that accompany HIPEC, tumors from five patients with high grade serous ovarian cancer were harvested from the omentum at time of debulking and after 90 minutes of HIPEC treatment. Specimens were rapidly dissociated into single cells and processed for single cell RNA-seq. Unbiased clustering identified 19 cell clusters that were annotated based on cellular transcriptome signatures to identify the epithelial, stromal, T and B immune cells, macrophages, and natural killer cell populations. Hallmark pathway analysis revealed heat shock, metabolic reprogramming, inflammatory, and EMT pathway enrichment in distinct cell populations upon HIPEC treatment. Collectively, our findings provide the foundation for mechanistic studies focused on how HIPEC orchestrates the ovarian cancer tissue response.

cancer biology↗

bioRxiv2020

Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy

Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death. Despite many patients achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. We assessed whether antibiotic (ABX) therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or ABX containing water (metronidazole, ampicillin, vancomycin, and neomycin) before being intraperitoneally injected with murine EOC cells. Stool was collected to confirm microbiome disruption and tumors were monitored, and cisplatin therapy was administered weekly until endpoint. EOC tumor-bearing mice demonstrate accelerated tumor growth and resistance to cisplatin therapy in ABX treated compared with nonABX treatment. Stool analysis indicated most gut microbial species were disrupted by ABX treatment except for ABX resistant bacteria. To test for role of the gut microbiome, cecal microbiome transplants (CMTs) of microbiota derived from ABX or nonABX treated mice were used to recolonize the microbiome of ABX treated mice. nonABX cecal microbiome was sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut derived tumor suppressor. Mechanistically, tumors from ABX treated compared to nonABX treated mice contained a high frequency of cancer stem cells that were augmented by cisplatin. These studies indicate an intact microbiome provides a gut derived tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment. SignificancePlatinum resistance is associated with poor prognosis and reduced therapeutic options for ovarian cancer patients. We identifed a tumor suppressive role of the gut microbiome that is disrupted upon antibiotic therapy.

cancer biology↗