Abstract Background Pancreatic ductal adenocarcinoma (PDAC) exhibits profound molecular heterogeneity and poor prognosis, necessitating novel tailored therapies. The basal and classical subtypes - driven by glycolysis versus lipid metabolism - have distinct prognostic implications warranting further characterization of their underlying transcriptional mechanisms. Methods Using spatial RNA sequencing we mapped PDAC molecular subtype heterogeneity, capturing spatially-resolved gene expression signatures and generating a comprehensive high-resolution dataset of 42,035 spatial spots. Subtype assignments were validated via multiplex immunofluorescence and quantitative analyses in patient-derived organoids and xenografts. Results Our analysis resolved cancer cell signatures, deconvoluted intra-tumoral heterogeneity, and delineated an evolutional classical-to-basal trajectory. We identified metabolically ‘hot’, high-grade tumor niches characterized by concurrent enrichment of glycolysis and lipogenesis across both subtypes, nominating them as subtype-agnostic therapeutic targets. Preclinical models demonstrated that despite the basal subtype’s glycolysis dependence, both classical and basal tumors are susceptible to glycolysis inhibition. Conclusion This work demonstrates that metabolic identity, spatial context, and tumor–stroma crosstalk are an inseparable triad that drives PDAC behavior. Our findings show that aggressive metabolic tumor niches can be targeted by glycolysis inhibition in a subtype-agnostic manner, challenging the dogma of subtype-specific therapeutic silos and highlighting highly adaptable energetic niches as reservoirs that drive tumor progression.

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with codeletion of the tumor-suppressor CDKN2A and the methylthioadenosine phosphorylase (MTAP) gene, but resistance limits their efficacy. Our study suggests that compensatory spliceosomal reprogramming contributes to adaptation to PRMT5 inhibition. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39). We investigated whether this response could be therapeutically leveraged by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic activity in cellular model systems. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared with single-agent treatments. Multiomics analysis revealed concomitant suppression of DNA repair and metabolic pathways. Collectively, our work support spliceosomal rewiring as a candidate adaptive response to PRMT5 inhibition and nominates RBM39 as a candidate therapeutic vulnerability, thereby supporting further evaluation of dual targeting of the splicing machinery. SIGNIFICANCE:Our study suggests that compensatory spliceosomal reprogramming occurs in response to PRMT5 inhibition. We investigated this vulnerability by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic antitumor activity in selected cellular PDAC models.

PURPOSE:To determine the benefit, measured as complete removal of a tumor so that no tumor cells are detectable during histopathologic examination of the resection margin (R0 resection rate), of induction chemotherapy plus chemoradiotherapy (CRT) compared with chemotherapy alone for unresectable pancreatic tumors. PATIENTS AND METHODS:CONKO-007, an investigator-initiated open-label, multicentric, phase III randomized clinical trial, enrolled 525 patients with unresectable tumors, and 495 patients received induction chemotherapy (402 with fluorouracil, irinotecan, and oxaliplatin [FOLFIRINOX] and 93 with gemcitabine). Patients without progression after 3 months of induction chemotherapy (n = 336) were randomly assigned for continuation of the same chemotherapy (n = 167) or CRT (n = 169; 50.4Gy concurrently with gemcitabine). Resectability was centrally reassessed by a panel of surgeons. Surgery was recommended if possible. After an interim analysis, the primary end point was changed from overall survival (OS) to overall R0 resection rate because of slow recruitment. The median follow-up was 76 months. Important planned secondary end points were R0 resection rate in the surgically treated population and OS. RESULTS:The primary end point (overall R0 resection rate) was not significantly different between treatment arms with 25% (43 of 169) in the CRT arm versus 18% in the chemotherapy arm (30 of 167; P = .113). Secondary end point analysis showed that surgery was performed equally often (P = .91); R0 resection rate in patients who underwent surgery was higher after CRT, 69.4% (43 of 62) compared with chemotherapy alone: 50.0% (30 of 60 patients, P = .04). Other parameters of resection (ratio of R0/R1/R2/no resection) also favored CRT (P = .02). No difference in OS was seen between treatment arms (hazard ratio [HR], 0.937 [95% CI, 0.747 to 1.174]; P = .57; randomly assigned intention-to-treat patients). Surgery was associated with longer OS (P < .001, HR, 0.525 [95% CI, 0.408 to 0.676]). CONCLUSION:Although not improving overall R0 resection rate or survival, CRT enables a R0 resection in surgically treated patients more often than chemotherapy alone.

Currently, no consensus exists regarding the definition of oligometastatic pancreatic ductal adenocarcinoma, its necessary diagnostic measures, and potential treatment approaches. To address these knowledge gaps, the OligoPanc project brought together an interdisciplinary group of experts to establish consensus using a modified Delphi process and clinical vignettes. Participants agreed that the number of metastatic lesions and the number of affected organs are key elements in defining oligometastatic pancreatic ductal adenocarcinoma. Specifically, up to three lesions in a single organ, either the liver or the lung, define oligometastatic pancreatic ductal adenocarcinoma and could be either synchronous or metachronous. Necessary diagnostics include a triple-phase contrast-enhanced CT scan of the chest and abdomen and MRI of the liver with a hepatocyte-specific contrast agent. In unclear cases, [18F]fluorodeoxyglucose-PET CT or MRI can be considered. A multidisciplinary tumour board is essential. Patient-intrinsic factors, including age, do not define oligometastatic disease but should be considered for any treatment decision. Systemic treatment before any local consolidative treatment, including surgery, stereotactic ablative radiotherapy, or other locally ablative techniques, is mandatory. The proposed definition should be incorporated into future trials to improve comparability and enable validation.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 13

Neoadjuvant chemoradiotherapy (CRT) constitutes a standard treatment for locally advanced rectal cancer (RC), frequently followed by radical surgical resection. Yet, therapeutic responses vary widely, and intrinsic radioresistance remains a major barrier to cure. To uncover actionable determinants of CRT response, we established a panel of patient-derived colorectal cancer cell lines (PDCLs) followed by integrated phenotypic and functional characterization. We identified metabolic reprogramming as a hallmark of radioresistance and, through orthogonal validation experiments, confirmed elevated glycolytic and mitochondrial ATP production in (chemo)irradiation-resistant PDCLs. The causative relationship of this association and its potential for therapeutic intervention was shown by subsequent drug screening, showing resistance to most of the applied drugs and revealing a critical dependency on the monocarboxylate transporter (MCT1) and the glucose transporter 1 (GLUT1). Metabolism-targeting compounds re-sensitized resistant PDCLs to irradiation; especially inhibition of GLUT1 exhibits a robust radiosensitizing activity across models. Concordantly, GLUT1 expression correlated with poor response to neoadjuvant CRT in our own RC patient cohort and various publicly available patient datasets. Collectively, our study defines metabolic dependency as a key driver of CRT resistance in RC, and reveals glycolysis- and lactate-transport-associated pathway activities as targetable vulnerabilities. These findings provide a mechanistic basis for patient stratification and support the development of metabolism-directed strategies to overcome (chemo)radioresistance in RC.

Despite recent advances in multimodal treatment strategies, radical tumor resection remains a cornerstone in the management of patients with rectal cancer. However, a substantial proportion of patients develop postoperative functional impairment known as low anterior resection syndrome (LARS). Emerging evidence suggests that robotic-assisted surgery may offer superior functional outcomes compared to other approaches. Therefore, this study aimed to compare the incidence and severity of LARS after robotic and open surgery using a patient-reported outcome measure (PROM). This retrospective, single-center cohort study included patients with primary adenocarcinoma of the sigmoid colon or rectum who underwent open or robotic oncological resection between 2014 and 2024. Eligible participants completed a standardized, validated questionnaire to assess their individual LARS score. The LARS scores were subsequently correlated with selected clinicopathological characteristics. LARS questionnaires were analyzed in 184 patients. The incidence of major LARS was comparable between open and robotic surgery (39.1