application-laparoscopic-programmatic-neurolymphatic-radical

Application of Laparoscopic Programmatic Neurolymphatic Radical Pancreaticoduodenectomy in Pancreatic Head Cancer

Laparoscopic pancreaticoduodenectomy (LPD) has become a widely adopted surgical approach for treating pancreatic head cancer. Traditional open ...

Southern Medical University

Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC.

circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis.

The tumor stroma of pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant and heterogeneous population of cancer-associated fibroblasts (CAFs), which are critically involved in chemoresistance. However, the underlying mechanism of CAFs in chemoresistance is unclear. Here, we show that CAF, a CAF subset derived from platinum-resistant PDAC patients, assumes an iCAF phenotype and produces more IL8 than CAF isolated from platinum-sensitive PDAC patients. CAF-derived IL8 promotes oxaliplatin chemoresistance in PDAC. Based on long noncoding RNA (lncRNA) profiling in tumor cells incubated with CAF-CM, we found that UPK1A-AS1, whose expression is directly induced by IL8/NF-kappa B signaling, functions as a chemoresistance-promoting lncRNA and is critical for active IL8-induced oxaliplatin resistance. Impressively, blocking the activation of UPK1A-AS1 expression increases the oxaliplatin sensitivity of tumor cells in vivo. Mechanistically, UPK1A-AS1 strengthens the interaction between Ku70 and Ku80 to facilitate nonhomologous end joining (NHEJ), thereby enhancing DNA double-strand break (DSB) repair. Clinically, UPK1A-AS1 expression is positively correlated with IL8 expression, a poor chemotherapeutic response and a shorter progression-free survival (PFS) time in advanced PDAC patients. Collectively, our study reveals a lncRNA-mediated mechanism of CAF-derived paracrine IL8-dependent oxaliplatin resistance and highlights UPK1A-AS1 as a potential therapeutic target.

Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair.

DNA double‑strand break repair is critically involved in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). Hepatocyte nuclear factor 1 homeobox A (HNF1A) has received increased attention regarding its role in cancer progression. The present study explored the role of HNF1A in oxaliplatin resistance in PDAC. The results revealed that HNF1A expression was negatively associated with oxaliplatin chemoresistance in PDAC tissues and cell lines. HNF1A inhibition promoted the proliferation, colony formation and stemness of PDAC cells, and suppressed their apoptosis. Furthermore, HNF1A inhibition switched nonhomologous end joining to homologous recombination, thereby enhancing genomic stability and oxaliplatin resistance. Mechanistically, HNF1A transcriptionally activates p53‑binding protein 1 (53BP1) expression by directly interacting with the 53BP1 promoter region. Upregulation of HNF1A and 53BP1 induced significant inhibition of PDAC growth and oxaliplatin resistance in patient‑derived PDAC xenograft models and orthotopic models. In conclusion, the findings of the present study suggested that HNF1A/53BP1 may be a promising PDAC therapeutic target for overcoming oxaliplatin resistance.

HNF1A regulates oxaliplatin resistance in pancreatic cancer by targeting 53BP1.

Cancer-associated fibroblasts (CAFs) play pivotal roles in chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Revealing the cross-talk network between tumor stroma and pancreatic cancer and developing effective strategies against oxaliplatin resistance are highly desired in the clinic.

Extracellular vesicle-packaged circBIRC6 from cancer-associated fibroblasts induce platinum resistance via SUMOylation modulation in pancreatic cancer.

Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)-dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer.

Extracellular vesicle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models.

Cancer-associated fibroblasts (CAFs) play a key role in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). However, the potential mechanisms by which CAFs promote chemotherapy resistance have not yet been explored. In this study, we found that circABCC4 (hsa_circ_0030582) was positively correlated with poor platinum-chemotherapeutic response and a shorter progression-free survival (PFS) time in late-stage PDAC patients. CircABCC4 enhanced the ability of CAFs to induce oxaliplatin resistance in pancreatic cancer cells through glycolysis reprogramming. Mechanistically, circABCC4 enhanced the interaction between PKM2 and KPNA2 to promote PKM2 nuclear translocation in CAFs, leading to the transcription of glycolysis-related genes. The glycolytic reprogramming of CAFs promoted the secretion of IL-8, which in turn enhanced DNA damage repair in pancreatic cancer. Blocking PKM2 nuclear translocation abolished circABCC4-driven oxaliplatin resistance of pancreatic cancer in vivo. Collectively, our study reveals a circRNA-mediated glycolysis reprogramming of CAFs to induce oxaliplatin resistance and highlights circABCC4 as a potential therapeutic target.

Glycolysis reprogramming in CAFs promotes oxaliplatin resistance in pancreatic cancer through circABCC4 mediated PKM2 nuclear translocation.

Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms underlying PNI in PDAC remain unclear.

N-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma.

Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. The recognized clinical impact of PNI highlights the need to better understand the molecular mechanisms underlying PNI-induced phenotypes. In this study, we isolated PNI-associated cancer-associated fibroblasts (pCAF), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared with non-PNI-associated CAFs. Single-cell, high-throughput sequencing and metabolomics data showed a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAF-derived lactate was absorbed by tumor cells, facilitating histone H3K18 lactylation. The lactate-induced epigenetic modification activated the transcription of neural invasion-associated genes, such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, which correlated with increased enzymatic activity and glycolytic flux. Targeting GAPDH and lactylation modifications significantly inhibited neural invasion in a genetically engineered mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Together, these findings provide critical insights into the role of CAFs in promoting PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.

Cancer-Associated Fibroblasts Foster a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer.

Liver diseases are established risk factors for hepatobiliary and pancreatic cancers. This study explores the relationship between liver disease and hepatobiliary-pancreatic cancers, focusing on transaminase levels and genetic susceptibility.

Article	Year
circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis. Molecular cancer\| PubMed ID: 35045883	2022
Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair. Oncogene\| PubMed ID: 35264742	2022
HNF1A regulates oxaliplatin resistance in pancreatic cancer by targeting 53BP1. International journal of oncology\| PubMed ID: 36825600	2023
Extracellular vesicle-packaged circBIRC6 from cancer-associated fibroblasts induce platinum resistance via SUMOylation modulation in pancreatic cancer. Journal of experimental & clinical cancer research : CR\| PubMed ID: 38012734	2023
Extracellular vesicle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models. Science translational medicine\| PubMed ID: 39018369	2024
Glycolysis reprogramming in CAFs promotes oxaliplatin resistance in pancreatic cancer through circABCC4 mediated PKM2 nuclear translocation. Cell death & disease\| PubMed ID: 39988592	2025
N-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR\| PubMed ID: 40119353	2025
Cancer-Associated Fibroblasts Foster a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer. Cancer research\| PubMed ID: 40138590	2025
Liver diseases, transaminases, and hepatobiliary-pancreatic cancer risk: a cohort and Mendelian randomisation study using data from UK Biobank. BMJ open gastroenterology\| PubMed ID: 40645641	2025

Rihua He

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