ESR1 fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes.

Breast cancer is a leading cause of female mortality and despite advancements in diagnostics and personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. Fortunately, identification of mechanisms of therapeutic resistance have rapidly transformed our understanding of cancer evasion and is enabling targeted treatment regimens. When the druggable estrogen receptor (ER, ESR1 ), expressed in two-thirds of all breast cancer, is exposed to endocrine therapy, there is risk of somatic mutation development in approximately 30% of cases and subsequent treatment resistance. A more recently discovered mechanism of ER mediated endocrine resistance is the expression of ER fusion proteins. ER fusions, which retain the protein's DNA binding domain, harbor ESR1 exons 1-6 fused to an in-frame gene partner resulting in loss of the 3' ER ligand binding domain (LBD). In this report we demonstrate that in no-special type (NST) and invasive lobular carcinoma (ILC) cell line models, ER fusion proteins exhibit robust hyperactivation of canonical ER signaling pathways independent of the ligand estradiol or anti-endocrine therapies such as Fulvestrant and Tamoxifen. We employ cell line models stably overexpressing ER fusion proteins with concurrent endogenous ER knockdown to minimize the influence of endogenous wildtype ER. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably the MYC pathway. The heterogeneous 3' fusion partners, particularly transcription factors SOX9 and YAP1 , evoked varying degrees of transcriptomic and cistromic activity that translated into unique phenotypic readouts. Herein we report that cell line activity is subtype-, fusion-, and assay-specific suggesting that the loss of the LBD, the 3' fusion partner, and the cellular landscape all influence fusion activity. Therefore, it will be critical to generate additional data on frequency of the ER fusions, in the context of the clinicopathological features of the tumor. Significance: ER fusion proteins exhibit diverse mechanisms of endocrine resistance in breast cancer cell lines representing the no special type (NST) and invasive lobular cancer (ILC) subtypes. Our emphasize upon both the shared and unique cellular adaptations imparted by ER fusions offers the foundation for further translational research and clinical decision making.

WCRC-25: A novel luminal Invasive Lobular Carcinoma cell line model.

Breast cancer is categorized by the molecular and histologic presentation of the tumor, with the major histologic subtypes being No Special Type (NST) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark pathognomonic loss of E-cadherin ( CDH1 ). Few ILC cell line models are available to researchers. Here we report the successful establishment and characterization of a novel ILC cell line, WCRC-25, from a metastatic pleural effusion from a postmenopausal Caucasian woman with metastatic ILC. WCRC-25 is an ER-negative luminal epithelial ILC cell line with both luminal and Her2-like features. It exhibits anchorage independent growth and haptotactic migration towards Collagen I. Sequencing revealed a CDH1 Q706* truncating mutation, together with mutations in FOXA1, CTCF, BRCA2 and TP53 , which were also seen in a series of metastatic lesions from the patient. Copy number analyses revealed amplification and deletion of genes frequently altered in ILC while optical genome mapping revealed novel structural rearrangements. RNA-seq analysis comparing the primary tumor, metastases and the cell line revealed signatures for cell cycle progression and receptor tyrosine kinase signaling. To assess targetability, we treated WCRC-25 with AZD5363 and Alpelisib confirming WCRC-25 as susceptible to PI3K/AKT signaling inhibition as predicted by our RNA sequencing analysis. In conclusion, we report WCRC-25 as a novel ILC cell line with promise as a valuable research tool to advance our understanding of ILC and its therapeutic vulnerabilities. Financial support: The work was in part supported by a Susan G Komen Leadership Grant to SO (SAC160073) and NCI R01 CA252378 (SO/AVL). AVL and SO are Komen Scholars, Hillman Foundation Fellows and supported by BCRF. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. This research was also supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. Finally, partial support was provided by the Magee-Womens Research Institute and Foundation, The Shear Family Foundation, and The Metastatic Breast Cancer Network.

Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments.

The prevalence of obesity and diabetes mellitus (DM) has been consistently increasing worldwide. Sharing powerful genetic and environmental features in their pathogenesis, obesity amplifies the impact of genetic susceptibility and environmental factors on DM. The ectopic expansion of adipose tissue and excessive accumulation of certain nutrients and metabolites sabotage the metabolic balance via insulin resistance, dysfunctional autophagy, and microbiome-gut-brain axis, further exacerbating the dysregulation of immunometabolism through low-grade systemic inflammation, leading to an accelerated loss of functional ß-cells and gradual elevation of blood glucose. Given these intricate connections, most available treatments of obesity and type 2 DM (T2DM) have a mutual effect on each other. For example, anti-obesity drugs can be anti-diabetic to some extent, and some anti-diabetic medicines, in contrast, have been shown to increase body weight, such as insulin. Meanwhile, surgical procedures, especially bariatric surgery, are more effective for both obesity and T2DM. Besides guaranteeing the availability and accessibility of all the available diagnostic and therapeutic tools, more clinical and experimental investigations on the pathogenesis of these two diseases are warranted to improve the efficacy and safety of the available and newly developed treatments.

Bariatric Surgery: Targeting pancreatic ß cells to treat type II diabetes.

Pancreatic ß-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved ß-cell function. In this article, we summarize the role of ß-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic ß-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse.

Robotic versus laparoscopic distal pancreatectomy on perioperative outcomes: a systematic review and meta-analysis.

Robotic surgery has become a promising surgical method in minimally invasive pancreatic surgery due to its three-dimensional visualization, tremor filtration, motion scaling, and better ergonomics. Numerous studies have explored the benefits of RDP over LDP in terms of perioperative safety and feasibility, but no consensus has been achieved yet. This article aimed to evaluate the benefits and drawbacks of RDP and LDP for perioperative outcomes. By June 2022, all studies comparing RDP to LDP in the PubMed, the Embase, and the Cochrane Library database were systematically reviewed. According to the heterogeneity, fix or random-effects models were used for the meta-analysis of perioperative outcomes. Odds ratio (OR), weighted mean differences (WMD), and 95% confidence intervals (CI) were calculated. A sensitivity analysis was performed to explore potential sources of high heterogeneity and a trim and fill analysis was used to evaluate the impact of publication bias on the pooled results. Thirty-four studies met the inclusion criteria. RDP provides greater benefit than LDP for higher spleen preservation (OR 3.52 95% CI 2.62-4.73, p < 0.0001) and Kimura method (OR 1.93, 95% CI 1.42-2.62, p < 0.0001) in benign and low-grade malignant tumors. RDP is associated with lower conversion to laparotomy (OR 0.41, 95% CI 0.33-0.52, p < 0.00001), and shorter postoperative hospital stay (WMD - 0.57, 95% CI - 0.92 to - 0.21, p = 0.002), but it is more costly. In terms of postoperative complications, there was no difference between RDP and LDP except for 30-day mortality (RDP versus LDP, 0.1% versus 1.0%, p = 0.03). With the exception of its high cost, RDP appears to outperform LDP on perioperative outcomes and is technologically feasible and safe. High-quality prospective randomized controlled trials are advised for further confirmation as the quality of the evidence now is not high.

The learning curve for robot-assisted distal pancreatectomy: a single-center experience of 301 cases.

Robotic distal pancreatectomy (RDP) has become a routine procedure in many pancreatic centers. This study aimed to describe a single-center experience with RDP since the first case, identify the learning curves of operation time and complication rate, and discuss the safety and feasibility of RDP. Methods: We collected and retrospectively analyzed the single-center surgical experience of 301 patients undergoing RDP at Peking Union Medical College Hospital (PUMCH) between 2012 and 2022 and described the change in operation proficiency and occurrence of perioperative complications in this observational study. The learning curve was assessed using the cumulative sum method. Results: We observed a three-phase pattern of RDP learning with operation time, complications, and postoperative pancreatic fistula as indicators and a two-phase pattern for spleening-preserving success. The mean operation time was 3.9 hours. The incidence rate of clinically significant postoperative pancreatic fistula (CRPOPF) was 17.9% and overall Clavien-Dindo complication rate (≥3) was 16.6%. The change of postoperative complicate rate was correlated with percentage of malignant cases. Conclusion: In the last decade, an evident decrease was seen in operation time, complication rate, and an increase in the spleen-preserving rate of distal pancreatectomy. With proper training, RDP is a safe and feasible procedure.

Mind the tributary of the canal: Are stents necessary for insulinoma enucleation in proximity to a prominent Duct of Santorini: A case report and literature review.

RATIONALE: We describe a case of insulinoma located extremely close to the accessory pancreatic duct (APD), but away from the main pancreatic duct (MPD). Previous studies showed insulinoma enucleation is a safe procedure for small benign tumors >3 mm distant from the MPD. However, in this case enucleation of the tumor led to unanticipated APD injury and grade B post-operative pancreatic fistula (POPF). We provide detailed records of clinical management and argue that enucleation of tumors near APD needs to be carefully weighed. PATIENT CONCERNS: The patient experienced a sudden increase of abdominal drain fluid and prolonged drainage time after a regular insulinoma enucleation surgery. DIAGNOSIS: APD damage during the enucleation. INTERVENTIONS: Drain fluid amylase concentration were regularly recorded and prolonged somatostatin analogs were administered. OUTCOMES: Amount of abdominal drain gradually decreased and the drain tube was removed on postoperative 37. LESSONS: Benign pancreatic tumor close to the APD need to be evaluated carefully and clinical evidence is warranted to affirm the necessity of placing a pancreatic duct stent before the surgery.

Management of Advanced Pancreatic Cancer through Stromal Depletion and Immune Modulation.

Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Unfortunately, therapeutic gains in the treatment of other cancers have not successfully translated to pancreatic cancer treatments. Management of pancreatic cancer is difficult due to the lack of effective therapies and the rapid development of drug resistance. The cytotoxic agent gemcitabine has historically been the first-line treatment, but combinations of other immunomodulating and stroma-depleting drugs are currently undergoing clinical testing. Moreover, the treatment of pancreatic cancer is complicated by its heterogeneity: analysis of genomic alterations and expression patterns has led to the definition of multiple subtypes, but their usefulness in the clinical setting is limited by inter-tumoral and inter-personal variability. In addition, various cell types in the tumor microenvironment exert immunosuppressive effects that worsen prognosis. In this review, we discuss current perceptions of molecular features and the tumor microenvironment in pancreatic cancer, and we summarize emerging drug options that can complement traditional chemotherapies.

Exosomes in Breast Cancer - Mechanisms of Action and Clinical Potential.

Extracellular vesicles (EV) are a heterogeneous group of cell-derived membrane vesicles comprising apoptotic bodies, microvesicles, and small EVs also called as exosomes. Exosomes when initially identified were considered as a waste product but the advancement in research techniques have provided insight into the important roles of exosomes in cell-cell communication, various biological processes and diseases, including cancer. As an important component of EVs, exosomes contain various biomolecules such as miRNAs, lipids, and proteins that largely reflect the characteristics of their parent cells. Notably, cancer cells generate and secrete many more exosomes than normal cells. A growing body of evidence suggests that exosomes, as mediators of intercellular cross-talk, play a role in tumorigenesis, cancer cell invasion, angiogenesis, tumor microenvironment (TME) formation, and cancer metastasis. As we gain more insights into the association between exosomes and cancer, the potential of exosomes for clinical use is becoming more intriguing. This review is focused on the role of exosomes in breast cancer, in terms of breast cancer biology, mechanism of action, potential as biomarkers, and therapeutic opportunities.