Pancreatic Cancer-Associated Fibroblasts: Where Do We Go from Here?

Pancreatic ductal adenocarcinoma is a deadly disease and is projected to become the second leading cause of cancer-related death by 2030. A major hallmark is the exuberant host response comprising the tumor microenvironment, of which, cancer-associated fibroblasts (CAF) are a prevalent component. Despite the gains in understanding of their heterogeneity and functionality from CAF studies in recent years, there are many unanswered questions surrounding this diverse population of cells.

"Tumor-selective treatment of metastatic pancreatic cancer with an engineered, probiotic living drug".

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for effective treatment, with systemic chemotherapy often proving inadequate due to poor drug delivery and the tumor's immunosuppressive microenvironment. Engineered bacteria present a novel approach to target PDAC, leveraging their ability to colonize tumors and deliver therapeutic payloads. Here, we engineered probiotic Nissle 1917 (EcN) to produce the pore-forming Theta toxin (Nis-Theta) and evaluated its efficacy in a preclinical model of PDAC.

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS.

Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression.

Unlabelled: The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC.

An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

Background & Aims: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4/NFATc1).

Methods: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4/NFATc1 cancers.

Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer.

The Kras;LSL-Trp53;Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA).

Aberrant NFATc1 signaling counteracts TGFβ-mediated growth arrest and apoptosis induction in pancreatic cancer progression.

Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor β (TGFβ) signaling and activation of the inflammatory transcription factor nuclear factor of activated T cells (NFATc1) in the regulation of transcriptional programs throughout PDAC progression.

Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients.

Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany.

NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation.

Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC) development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR) or induction of Sox9 expression, are required for tumor formation.