Pancreatic Ductal Adenocarcinoma

This study provides a spatially resolved molecular map of IPMN progression, delineating key transcriptomic and immune signatures. These findings advance the understanding of IPMN biology and highlight potential biomarkers for risk stratification and therapeutic strategies.

Our data further demonstrated that pharmacological or genetic inhibition of c-Myc effectively reversed the resistance phenotype mediated by HDAC5 loss, suggesting a therapeutic strategy centered on "KRAS-MYC dual-node blockade." Furthermore, the expression levels of HDAC5 and the acetylation status of c-Myc may serve as potential biomarkers for predicting the therapeutic response to MRTX1133. These findings provide insights into overcoming resistance to KRASG12D inhibitors and offer potential biomarkers and combinatorial therapeutic strategies for precision treatment of PDAC.

Additionally, fostamatinib inhibited PDAC cell proliferation even in the absence of viral infection, while ruxolitinib did not. Our data suggest that fostamatinib may be repurposed as an effective drug that enhances OV therapy in PDAC by promoting OV replication and suppressing tumor growth.

The effector Th and Tc are the dominant prognostic T cell subsets in PDAC, whereas Treg abundance alone is an incomplete surrogate of immunosuppression. These findings describe the immunobiological landscape of PDAC.

Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval for NGR1 fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches.

We conclude that PDAC is characterized by increased MAPK STP activity in combination with high Ki67 and increased activity of developmental pathways (Wnt, Hedgehog, Notch, TGFβ). Drugs targeting specific STPs will be evaluated in PDAC model systems to develop new therapies for PDAC.

P=N/A, N=96, Completed, Changhai Hospital | Recruiting --> Completed | Phase classification: P2 --> PN/A | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Dec 2023 --> Aug 2025

We described the genomic landscape of KRASG12D-mutant CRC and PDAC, demonstrating that cases often have additional oncogenic alterations linked to resistance to KRAS inhibition. These alterations are also associated with a worse prognosis. Recognizing these alterations may inform new therapeutic strategies. Further studies are warranted to validate these findings in ongoing clinical trials.

EMP1 plays a crucial role in the pathogenesis of PDAC, as it contributes to the proliferative and metastatic characteristics of PDAC. This study suggests that EMP1 may be a potential therapeutic target gene for aggressive disease.

Using the ART-TIME approach, we identify a AhR-ARNT-mediated co-signaling mechanism between PD-1 and CD2 as a driver in immune evasion of pancreatic ductal adenocarcinoma. Our study advances the field of hybrid organoid engineering, offers opportunities for the construction and modelling of artificial tumour environments, and marks a step towards the design of functional living/non-living cytomimetic materials.

Disrupting this axis induces ferroptotic death and impairs PDAC development. Our study reveals a previously unrecognized mechanism in which HERVH-derived eRNAs regulate ferroptosis via super-enhancer-mediated transcriptional reprogramming and highlights the KLF5/HERVH/ALDH1A3 pathway as a potential therapeutic target in PDAC.

Acting as a glycan rheostat, GNASR201C elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3'-sulfo-LeA/C are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.