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BackgroundTargeting protein for Xenopus kinesin-like protein 2 (TPX2) overexpression in human tumours is associated with increased malignancy. Its effect on gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) has not been studied yet.MethodsThe prognostic impact of TPX2 expression was examined in the tumour tissue of 139 patients with advanced PDAC (aPDAC) treated within the AIO-PK0104 trial or translational trials and of 400 resected PDAC (rPDAC) patients. The findings were validated using RNAseq data of 149 resected PDAC patients.ResultsIn the aPDAC cohorts, 13.7% of all samples showed high TPX2 expression, conferring significantly shorter progression-free survival (PFS, HR 5.25, P < 0.001) and overall survival times (OS, HR 4.36, P < 0.001) restricted to gemcitabine-based treated patients (n = 99). In the rPDAC cohort, 14.5% of all samples showed high TPX2 expression, conferring significantly shorter disease-free survival times (DFS, HR 2.56, P < 0.001) and OS times (HR 1.56, P = 0.04) restricted to patients treated with adjuvant gemcitabine. RNAseq data from the validation cohort confirmed the findings.ConclusionsHigh TPX2 expression may serve as a negative predictor of gemcitabine-based palliative and adjuvant chemotherapy in PDAC and could be used to inform clinical therapy decisions.Clinical trial registryThe clinical trial registry identifier is NCT00440167.

Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15–25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.

Pancreatitis, or inflammation of the pancreas, is a common gastrointestinal condition. While often acute and self-resolving, it can become chronic and promote pancreatic ductal adenocarcinoma (PDAC), the third deadliest cancer worldwide. Pancreatitis is accompanied by morphological and molecular changes, notably immune cell infiltration, fibrosis, and acinar-to-ductal metaplasia (ADM). ELP3, the catalytic subunit of the Elongator complex, modifies wobble uridine tRNAs to optimize codon translation rates. It is critical to inflammatory processes and cancer in multiple organ systems, yet its role in the pancreas has not been investigated. This study aimed to investigate the expression and implication of ELP3 during pancreatitis induced in mice via repetitive caerulein injections. Acute pancreatitis was accompanied by increased expression of ELP3, which was mainly detected in pancreatic epithelial cells. To assess its function, we genetically inactivated Elp3 in pancreatic epithelial cells. Elp3 deficiency had no detectable effects on pancreas homeostasis, on the initiation and resolution of acute pancreatitis, on the development of chronic pancreatitis, or on pancreatitis-induced PDAC initiation. Our findings indicate that ELP3 is dispensable in pancreatic formation, inflammation and PDAC initiation. Future studies should explore its role in non-epithelial cells and its potential involvement in other PDAC hallmarks, such as therapy resistance.

In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair). PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models. The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction. The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.

SMAD4, a tumor suppressor gene, is lost in up to 60%–90% of pancreatic adenocarcinomas (PDAs). Loss of SMAD4 allows tumor progression by upregulating autophagy, a cell survival mechanism that counteracts apoptosis and allows intracellular recycling of macromolecules. Hydroxychloroquine (HCQ) is an autophagy inhibitor. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. We retrospectively analyzed the SMAD4 status of patients with PDA enrolled in two prospective clinical trials evaluating pre‐operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab‐paclitaxel +/− HCQ evaluated Evans Grade histopathologic response (NCT01978184). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log‐rank test were used to assess response and survival. Fifty‐two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty‐five patients had SMAD4 loss (48%). 76% of HCQ‐treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (p = 0.006). Although loss of SMAD4 has been associated with worse outcomes, in the current study, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ‐treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18). The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship among SMAD4, autophagy, and treatment outcomes in PDA is warranted.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, underscoring the urgent need for in-depth biological research. The phenomenon of alternative RNA splicing dysregulation is a common hallmark in cancer, including PDAC, presenting new avenues for understanding and developing diagnostic and therapeutic tools. Our research focuses on EIF4A3, a core component of the Exon Junction Complex intimately linked to RNA splicing, and its role in PDAC. EIF4A3 is overexpressed in PDAC tissue and associated to clinical parameters of malignancy and poorer patient survival. Mechanistically, exploration of PDAC RNA-seq data unveiled the link of EIF4A3 to diverse malignancy processes, consistent with its association to key molecular pathways. EIF4A3 targeting in vitro decreased essential functional tumor features such as proliferation, migration, colony formation and sphere formation, while its in vivo targeting reduced tumor growth. EIF4A3 silencing in PDAC cell lines severely altered its transcriptional and spliceosomic landscapes, as shown by RNA-seq analyses, suggesting a role for EIF4A3 in maintaining RNA homeostasis. Our results indicate that EIF4A3 dysregulation in PDAC has a pleiotropic regulatory role on RNA biology, influencing key cellular functions. This paves the way to explore its potential as novel biomarker and actionable target candidate for this lethal cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro‐metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell‐free DNA (cfDNA) as an early biomarker of micro‐metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour‐restricted genetic PI3Kα‐selective inhibition prevented macro‐metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP 3 , with a selective decrease of C36:2 PI‐3,4,5‐P 3 . Tumoural PI3Kα inactivation prevented the accumulation of pro‐tumoural CD206‐positive macrophages in the tumour‐adjacent tissue. Tumour cell‐intrinsic PI3Kα promotes pro‐metastatic features that could be pharmacologically targeted to delay macro‐metastatic evolution. SYNOPSIS Primary tumours from metastatic PDAC patients are characterized by a selective transcriptomics signature, including a gene signature representative of PI3Kα activation, which predicts tumour evolution. PDAC tumour cell migration is regulated by a minimal PI3Kα activity. PI3Kα tumour cell intrinsic activity is triggered by oncogenic mutations and by a tumoural context such as secreted FGF receptor ligands. Macrophage TNFα secretion is promoted by PI3Kα activity‐induced IL‐3 in tumour cell; conversely, tumour cell migration is promoted by TNFα. Higher level of cfDNA with KRAS mutation in pancreatic cancer patients is associated with increased PI3K activity markers in primary tumour. Evolution from micro‐metastatic disease to macro‐metastatic stage is dependent on PI3Kα activity and is prevented by PI3Kα pharmacological inhibition. Graphical Abstract Primary tumours from metastatic PDAC patients are characterized by a selective transcriptomics signature, including a gene signature representative of PI3Kα activation, which predicts tumour evolution.

Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF , chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development ( FOXA2/3 , PDX1 and MNX1 ). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine ( NR5A2 and RBPJL ), and endocrine differentiation ( NEUROD1 and NKX2-2 ). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development. An integrated genomic analysis of 456 human pancreatic ductal adenocarcinomas identifies four subtypes defined by transcriptional expression profiles and show that these are associated with distinct histopathological characteristics and differential prognosis. Pancreatic cancer genomics Sean Grimmond and colleagues report integrated genomic analysis of 456 pancreatic ductal adenocarcinomas. They identify four subtypes defined by expression profiles, characterize their transcriptional networks, and show that these are associated with distinct histopathological characteristics and differential survival.

A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA–lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran 1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA–lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells ( n  = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells ( n  = 8; median RFS 13.4 months; P   =  0.007). In responders, autogene cevumeran induces CD8 + T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8 + T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA–lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination. In a phase 1 trial, patients with pancreatic ductal adenocarcinoma who were treated with surgery and bespoke neoantigen mRNA vaccines combined with anti-PD-L1 and chemotherapy exhibited marked long-lived persistence of neoantigen-specific CD8 + T cell clones, which correlated with prolonged recurrence-free survival at a 3.2-year follow-up.