TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma

The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (DeltaNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types

What can whiskers tell us about mammalian evolution, behaviour, and ecology?

Most mammals have whiskers; however, nearly everything we know about whiskers derives from just a handful of species, including laboratory rats Rattus norvegicus and mice Mus musculus, as well as some species of pinniped and marsupial. We explore the extent to which the knowledge of the whisker system from a handful of species applies to mammals generally. This will help us understand whisker evolution and function, in order to gain more insights into mammalian behaviour and ecology. This review is structured around Tinbergen’s four questions, since this method is an established, comprehensive, and logical approach to studying behaviour. We ask: how do whiskers work, develop, and evolve? And what are they for? While whiskers are all slender, curved, tapered, keratinised hairs that transmit vibrotactile information, we show that there are marked differences between species with respect to whisker arrangement, numbers, length, musculature, development, and growth cycles. The conservation of form and a common muscle architecture in mammals suggests that early mammals had whiskers. Whiskers may have been functional even in therapsids. However, certain extant mammalian species are equipped with especially long and sensitive whiskers, in particular nocturnal, arboreal species, and aquatic species, which live in complex environments and hunt moving prey. Knowledge of whiskers and whisker use can guide us in developing conservation protocols and designing enriched enclosures for captive mammals. We suggest that further comparative studies, embracing a wider variety of mammalian species, are required before one can make large-scale predictions relating to evolution and function of whiskers. More research is needed to develop robust techniques to enhance the welfare and conservation of mammals

Organoid models for translational pancreatic cancer research

Despite recent advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) still retains the worst survival rate of common malignancies. Late diagnosis and lack of curative therapeutic options are the most pressing clinical problems for this disease. Therefore, there is a need for patient models and biomarkers that can be applied in the clinic to identify the most effective therapy for a patient. Pancreatic ductal organoids are ex-vivo models of PDAC that can be established from very small biopsies, enabling the study of localized, advanced, and metastatic patients. Organoids models have been applied to pancreatic cancer research and offer a promising platform for precision medicine approaches

Exploring the role of glycosylation in pancreatic diseass

Pancreatic ductal adenocarcinoma (PDA) is almost uniformly lethal and surgical intervention is the only cure. Unfortunately, most patients are ineligible for resection because of the advanced stage of disease by the time of diagnosis. This is due in part to the lack of diagnostic tools, especially for families with elevated risk. The PDA biomarker, CA19-9, is measured in the blood to follow tumor burden longitudinally, but is neither sensitive nor specific enough to be used for diagnosis. The use of CA19-9 in PDA diagnosis is problematic given the elevation of CA19-9 in benign pancreatic disease, such as pancreatitis. While CA19-9 has been traditionally used as a diagnostic, retrospective studies reported that PDA patients who maintain a CA19-9 negative/low status have a significantly longer survival relative to those with higher CA19-9 levels in multivariate analyses. The functional significance of CA19-9 to PDA initiation, maintenance, and progression remains unclear due in part to the absence of this carbohydrate modification in mice. We found that expression of CA19-9 in the mouse pancreas is sufficient to induce pancreatitis, a benign proliferative condition that often confounds the diagnosis of PDA. Specifically, CA19-9 elevation resulted in rapid elevation of pancreatic enzymes in the blood, pancreatic infiltration of immune cells, acinar-to-ductal metaplasia and atrophy, as well as increased proliferation. Furthermore, we explored the utility of CA19-9 as a therapeutic target for both acute and chronic pancreatitis. This avenue of treatment strategy exhibits potential given that a pilot study demonstrated that turning off CA19-9 expression results in the normalization of pancreatic enzyme levels within four days following an acute episode of pancreatitis. Future work will focus on how elevation of this glycosylation modification mediates the development of pancreatitis by identifying the signaling pathways that are altered upon CA19-9 expression. In addition, we will explore the efficacy of therapeutically targeting CA19-9 in both pancreatitis and PDA with a larger goal of delineating the role of CA19-9 in pancreatic diseas

Exploring the role of glycosylation in pancreatic diseass

Pancreatic ductal adenocarcinoma (PDA) is almost uniformly lethal and surgical intervention is the only cure. Unfortunately, most patients are ineligible for resection because of the advanced stage of disease by the time of diagnosis. This is due in part to the lack of diagnostic tools, especially for families with elevated risk. The PDA biomarker, CA19-9, is measured in the blood to follow tumor burden longitudinally, but is neither sensitive nor specific enough to be used for diagnosis. The use of CA19-9 in PDA diagnosis is problematic given the elevation of CA19-9 in benign pancreatic disease, such as pancreatitis. While CA19-9 has been traditionally used as a diagnostic, retrospective studies reported that PDA patients who maintain a CA19-9 negative/low status have a significantly longer survival relative to those with higher CA19-9 levels in multivariate analyses. The functional significance of CA19-9 to PDA initiation, maintenance, and progression remains unclear due in part to the absence of this carbohydrate modification in mice. We found that expression of CA19-9 in the mouse pancreas is sufficient to induce pancreatitis, a benign proliferative condition that often confounds the diagnosis of PDA. Specifically, CA19-9 elevation resulted in rapid elevation of pancreatic enzymes in the blood, pancreatic infiltration of immune cells, acinar-to-ductal metaplasia and atrophy, as well as increased proliferation. Furthermore, we explored the utility of CA19-9 as a therapeutic target for both acute and chronic pancreatitis. This avenue of treatment strategy exhibits potential given that a pilot study demonstrated that turning off CA19-9 expression results in the normalization of pancreatic enzyme levels within four days following an acute episode of pancreatitis. Future work will focus on how elevation of this glycosylation modification mediates the development of pancreatitis by identifying the signaling pathways that are altered upon CA19-9 expression. In addition, we will explore the efficacy of therapeutically targeting CA19-9 in both pancreatitis and PDA with a larger goal of delineating the role of CA19-9 in pancreatic diseas

Patient-derived organoid models help define personalized management of gastrointestinal cancer

BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models. METHODS: A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained. RESULTS: Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine-needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. CONCLUSION: High-throughput drug screening on organoids, combined with next-generation sequencing, proteomic analysis and other state-of-the-art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side-effects

Single-Pass vs 2-Pass Endoscopic Ultrasound-Guided Fine-Needle Biopsy Sample Collection for Creation of Pancreatic Adenocarcinoma Organoids

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancies, with a 5-year survival rate <8%.1,2 Suspicious lesions are typically diagnosed via endoscopic ultrasound-guided fine-needle aspiration or endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB).3 Fewer needle passes decreases the risk of postprocedure complications, including pancreatitis and hemorrhage, while allowing additional needle passes to be used for adjuvant tissue testing, such as organoid creation and DNA sequencing