Intestinal tract development is a coordinated process involving signaling among the progenitors and developing cells from all three germ layers. Development of endoderm-derived intestinal epithelium ...has been shown to depend on epigenetic modifications, but whether that is also the case for intestinal tract cell types from other germ layers remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced numbers of ectoderm-derived enteric neurons and severe disruption of mesoderm-derived intestinal smooth muscle. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron precursors and cell-non-autonomously in surrounding intestinal cells, consistent with what is known about signaling interactions between these cell types that promote one another’s development. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neurons and smooth muscle progenitors. dnmt1 mutants have fewer enteric neurons and disrupted intestinal smooth muscle compared to wildtypes. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important to coordinate intestinal tract development, provides the first demonstration that these genes influence development of the ENS, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.
•uhrf1 and dnmt1 mutants have disrupted enteric neurons and intestinal smooth muscle.•Uhrf1 functions cell-autonomously and cell-non-autonomously during ENS development.•Epigenetic modifiers Uhrf1 and Dnmt1 function together during intestinal development.
Gynecological malignancies are a significant cause of morbidity and mortality across the globe. Due to delayed presentation, gynecological cancer patients are often referred late in the disease's ...course, resulting in poor outcomes. A considerable number of patients ultimately succumb to chemotherapy-resistant disease, which reoccurs at advanced stages despite treatment interventions. Although efforts have been devoted to developing therapies that demonstrate reduced resistance to chemotherapy and enhanced toxicity profiles, current clinical outcomes remain unsatisfactory due to treatment resistance and unfavorable off-target effects. Consequently, innovative biological and nanotherapeutic approaches are imperative to strengthen and optimize the therapeutic arsenal for gynecological cancers. Advancements in nanotechnology-based therapies for gynecological malignancies offer significant advantages, including reduced toxicity, expanded drug circulation, and optimized therapeutic dosing, ultimately leading to enhanced treatment effectiveness. Recent advances in nucleic acid therapeutics using microRNA, small interfering RNA, and messenger RNA provide novel approaches for cancer therapeutics. Effective single-agent and combinatorial nucleic acid therapeutics for gynecological malignancies have the potential to transform cancer treatment by giving safer, more tailored approaches than conventional therapies. This review highlights current preclinical studies that effectively exploit these approaches for the treatment of gynecological malignant tumors and malignant ascites.
Ovarian Cancer Treatment
In article number 2204436 by Daniel L. Marks, Oleh Taratula, and co‐workers, follistatin mRNA delivered by lipid nanoparticles targets ovarian cancer clusters dispersed in ...the peritoneal cavity of mice. When combined with platinum chemotherapy, the proposed treatment may allow complete cytoreduction, enhance resilience to the iatrogenic burden of chemotherapeutic intervention, increase overall survival, and minimize chemotherapy‐induced muscular atrophy and cancer‐associated cachexia.
Abstract
The sympathetic nervous system controls the fight or flight response and regulates the physiological function of many organs. Therefore, a dysfunctional adrenergic input not only impairs ...normal physiology but also contributes to the ongoing pathology observed in numerous chronic conditions. This is especially true for patients suffering from cancer and cancer-associated cachexia, a multifactorial syndrome characterized by weight loss, anorexia, and increased metabolic rate. Many studies in cancer cachexia animal models demonstrated an elevated adrenergic tone, mediating white adipose tissue browning and elevating resting metabolic rate. Recent clinical studies also demonstrated signs of autonomic dysfunction in cancer cachexia patients. Indeed, treating cancer cachexia patients with beta blockers showed promising results by preventing loss of body mass, further highlighting a role for adrenergic dysfunction in driving cachexia pathophysiology. However, the mediators of adrenergic dysfunction in cancer cachexia patients remain poorly understood. To investigate this question, we used a murine model of pancreatic ductal adenocarcinoma (PDAC) associated cachexia and performed bulk RNA-sequencing of stellate ganglia (SG) (n=6) and celiac-superior mesenteric ganglia (CG-SMG) (n=6). The SG provide sympathetic innervation to the heart and brown adipose tissue, which both undergo atrophy in cancer cachexia patients. The CG-SMG provide sympathetic innervation to the liver, one of the major metabolic organs that goes awry during cachexia, along with the pancreas and the tumor. By analyzing these ganglia, we aimed to determine the molecular basis for sympathetic hyperactivity in cancer cachexia. Gene ontology analysis of our RNA-seq data revealed an enrichment of pathways associated with leukocyte migration and activation as well as regulation of inflammatory pathways (p-value < 0.0001). We complemented our RNA-seq studies with immunohistochemistry experiments of SG and CG-SMG and discovered a significant recruitment of CD45+ immune cells (Sham average: 100.6, PDAC average: 599.8; p-value < 0.001). These immune cells alter the inflammatory milieu within sympathetic ganglia, thereby providing a mechanism for dysfunctional adrenergic outflow. Considering prior studies highlighted the interaction between immune cells and sympathetic outflow in models of obesity, hypertension, and heart failure, we believe our observations point to a possible mechanism for autonomic dysfunction in cancer cachexia patients.
Citation Format: Parham Diba, Mason A. Norgard, Xinxia Zhu, Tetiana Korzun, Peter R. Levasseur, Daniel L. Marks. Pancreatic cancer cachexia is associated with infiltration of immune cells into sympathetic ganglia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 359.
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