Improvement of outcome in patients with pancreatic ductal adenocarcinoma (PDAC) requires exploration of novel therapeutic targets. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology, yet SUMOylation occurs in a variety of cell types. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical-stage compound, TAK-981. In contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit conferred by TAK-981 in vivo is dependent on the presence of T cells, suggesting that induction of adaptive antitumor immunity is an important antitumor effect of SUMOylation inhibition in vivo. To understand how this adaptive antitumor immunity is promoted, we investigated how SUMOylation inhibition in vivo alters major cell types/subtypes and their communications in the PDAC tumor microenvironment by performing transcriptomic analyses at single-cell resolution, which allowed mapping of cells in our orthotopic mouse model to cells in human PDAC tumors based on gene expression profiles. Findings are further validated by flow cytometry, immunofluorescence, IHC, western blots, and qPCR. The single-cell transcriptome dataset provided here suggests several combination strategies to augment adaptive immune responses that are necessary for durable disease control in patients with PDAC.

Aim: Early‐onset colorectal cancer (EOCC), defined as colorectal cancer (CRC) diagnosed in patients under the age of 50, has increased alarmingly in Western countries in recent decades. Although risk factors, diagnostics and treatment approaches have been studied, the subjective experiences of EOCC patients remain underexplored. This study aimed to identify patient‐perceived challenges and their unmet needs in Switzerland, a country with a high‐resource healthcare system with minimal waiting times for investigations and comprehensive healthcare coverage. Method: Nineteen semi‐structured interviews were conducted between 09/2023 and 06/2024 with EOCC patients following a constructivist grounded theory approach. Results: Participants from all cancer stages and aged between 30 and 50 years were recruited. We developed three main themes from the collected data: diagnostic delay, coping mechanisms and stigmatisation. Despite access to a well‐resourced healthcare system, study participants experienced diagnostic delays, indicating the need for increased physician awareness and improved risk‐based screening for high‐risk individuals. Participants' key coping strategies included self‐advocacy and participating in medical decision‐making, like prioritising fertility preservation over rushed treatment. Participants reported fear of stigmatisation and isolation after being diagnosed. Such stigma manifested in concerns over alopecia or living with an ostomy. Finally, participants experienced an internal shift in personal priorities resulting in post‐traumatic growth despite cancer diagnosis Conclusions: EOCC challenges current clinical practices. Better physician awareness, risk‐factor‐based screening policies, integrated discussions about individual treatment such as potential fertility issues and targeting stigma are critical for improving the EOCC patients' journey.

Background: Early-onset colorectal cancer (EOCC), defined as CRC in patients under 50, is rising alarmingly in Western countries. This study explores key differences in clinical profiles, socioeconomic factors, and oncological treatments between EOCC and later-onset colorectal cancer (LOCC) patients. Patients and methods: This multicenter cohort study analyzed CRC patients treated from January 2023 to June 2024 at 11 centers in Northwestern Switzerland. Patients with confirmed CRC were included, while exclusions applied to secondary CRC, unconfirmed cases, and those unable to consent. Statistical analyses included descriptive methods, Fisher’s exact test, Kruskal–Wallis tests, and logistic regression ( P ≤ 0.05). Results: Among 764 patients, 10.5% had EOCC and 89.5% LOCC. Mean age was 42.1 for EOCC and 70.8 for LOCC. EOCC patients were more often non-Swiss (67.5% vs. 32.2%, P < 0.001), faced greater financial hardship ( P < 0.001), consumed more glucose (>5 units/week) (48.8% vs. 35.2%, P = 0.02), and had more second-degree relatives with CRC ( P = 0.05). EOCC symptoms included abdominal pain (54.6%) and rectal bleeding (50.6%), while LOCC presented with rectal bleeding (35.4%) and bowel habit changes (25.3%). EOCC had longer diagnostic delays (7.2 vs. 4.2 months, P = 0.03) and reached a higher UICC stage (IIIC vs. IIIA). Adjuvant therapy was more frequent in EOCC for colon (52.4% vs. 35.2%, P = 0.04) and rectal cancer (58.3% vs. 33.3%, P = 0.02). Defunctioning ostomies were more common in EOCC (13.2% vs. 3.2%, P = 0.01). EOCC had shorter hospital stays (8.66 vs. 11.43 days, P = 0.05), but intensive care unit stays, complications, lymph node retrieval, and operation times were similar. Conclusion: These findings emphasize the need for tailored screening protocols and personalized management strategies to address the unique challenges faced by patients under 50 and to improve outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined.

Improvement of outcome in patients with pancreatic ductal adenocarcinoma (PDAC) requires exploration of novel therapeutic targets. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology, yet SUMOylation occurs in a variety of cell types. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical-stage compound, TAK-981. In contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit conferred by TAK-981 in vivo is dependent on the presence of T cells, suggesting that induction of adaptive antitumor immunity is an important antitumor effect of SUMOylation inhibition in vivo. To understand how this adaptive antitumor immunity is promoted, we investigated how SUMOylation inhibition in vivo alters major cell types/subtypes and their communications in the PDAC tumor microenvironment by performing transcriptomic analyses at single-cell resolution, which allowed mapping of cells in our orthotopic mouse model to cells in human PDAC tumors based on gene expression profiles. Findings are further validated by flow cytometry, immunofluorescence, IHC, western blots, and qPCR. The single-cell transcriptome dataset provided here suggests several combination strategies to augment adaptive immune responses that are necessary for durable disease control in patients with PDAC.