Biology subjects

Worley, B. L.

Publications and source records attributed to Worley, B. L..

3 recordsLinked to original sources

bioRxiv2024

Loss of the predicted cell adhesion molecule MPZL3 promotes EMT and chemoresistance in ovarian cancer

Myelin protein zero-like 3 (MPZL3) is an Immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, where the MPZL3 gene resides, is frequently observed in cancer, and MPZL3 copy number alterations are frequently detected in tumor specimens. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, where both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. While high and low MPZL3 expressing populations were similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely displayed decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knock-down leads to strong upregulation of vimentin and an EMT gene signature that is associated with poor patient outcomes. Moreover, MPZL3 is necessary for homotypic cancer cell adhesion, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. In addition, MPZL3 loss abrogated cell cycle progression and proliferation. This was associated with increased resistance to Cisplatin and Olaparib and reduced DNA damage and apoptosis in response to these agents. Enhanced Cisplatin resistance was further validated in vivo. These data demonstrate for the first time that MPZL3 acts as an adhesion molecule and that MPZL3 loss results in EMT, decreased proliferation, and drug resistance in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients.

cancer biology↗

bioRxiv2022

IL-6/STAT3 signaling drives early-stage pancreatic cancer cachexia via suppressed ketogenesis

Cancer cachexia is highly prevalent in patients with pancreatic ductal adenocarcinoma (PDAC). Although advanced cachexia is associated with inflammatory signaling, the early events driving wasting are poorly defined. Using an orthotopic mouse model of PDAC, we find that early cachexia is defined by a pronounced vulnerability to undernutrition, characterized by increased skeletal muscle wasting. PDAC suppresses lipid beta oxidation and impairs ketogenesis in the liver, which coordinates the adaptive response to nutritional scarcity. When PDAC mice are fed ketogenic diet, this effect is reversed, and muscle mass is preserved. Furthermore, physiologic levels of ketones are sufficient to protect myotubes against PDAC-associated wasting. Interleukin-6 (IL-6) drives liver metabolic reprogramming, and hepatocyte-specific loss of Signal Transducer and Activator of Transcription 3 (STAT3) is sufficient to prevent PDAC-associated muscle loss. Together, these studies define a key role for the liver in cachexia development and directly link skeletal muscle homeostasis to hepatic lipid oxidation.

cancer biology↗

bioRxiv2019

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells.

Cells must alter their antioxidant capacity for maximal metastatic potential. However, the antioxidant adaptations required for transcoelomic metastasis, which is the passive dissemination of cancer cells in the peritoneal cavity as seen in ovarian cancer, have largely remained unexplored. Contradicting the need for oxidant scavenging by tumor cells is the observation that expression of the nutrient stress sensor and regulator of mitochondrial antioxidant defenses, SIRT3, is suppressed in many primary tumors. We discovered that this mitochondrial deacetylase is however, upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase SOD2. This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent transcriptional increases in SOD2 during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 up-regulation and SIRT3-mediated oxidant scavenging following matrix detachment are required for anoikis resistance in vitro, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.

cancer biology↗