LaRue-Nolan, Kayla C.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is a devastating disease predicted to be the second leading cause of cancer deaths by 2040. Despite extensive molecular characterization, therapeutic targeting of this disease remains largely unsuccessful. Thus, an increased understanding of the mechanisms driving malignant features of PDAC is critical for the development of new therapeutic strategies. Of these, cancer cell survival is a central malignant event in PDAC contributing to disease initiation, progression, and response to therapy. To date, the majority of cell survival mechanisms associated with PDAC biology has highlighted the role of cytoplasmic and extracellular factors, making the role of nuclear elements understudied. Our preliminary data has demonstrated evidence of a novel mechanism regulating nuclear envelope stability, a key process contributing to cell survival. Work from our lab has shown that oncogenic KRAS, the major genetic driver of PDAC and present in ∼40% of cases, is sufficient to reduce the incidence of spontaneous nuclear envelope rupture, a measure of nuclear envelope stability. Using laser-induced nuclear envelope rupture revealed the presence of oncogenic KRAS decreases the extent of ruptures, suggesting an axis downstream of oncogenic KRAS is key for regulation of nuclear stability. Analysis of nuclear lamins, key intermediate filaments providing structure to the nuclear envelope, revealed only A-type lamins, not B-type, are associated with overall PDAC survival and enrich at the nuclear periphery downstream of oncogenic KRAS. Furthermore, BioID protein-protein interaction assays to examine the oncogenic KRAS-induced effects on nuclear repair proteins identified an increase in interaction between Lamin A and Emerin. Knock-down of either protein results in increases in nuclear envelope spontaneous ruptures. Together our findings provide a novel oncogenic KRAS-Lamin A-Emerin axis controlling the nuclear stability in PDAC, which can serve as a new therapeutic avenue to improve PDAC treatment outcomes. Citation Format: Kayla C. LaRue-Nolan, Ashley N. Sigafoos, Luis F. Flores, Kyle J . Roux, Martin E. Fernandez-Zapico. The role of Lamin A in pancreatic cancer nuclear envelope stability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A059.

For over a century, scientists reported the disruption of normal nuclear shape and size in cancer. These changes have long been used as tools for diagnosis and staging of malignancies. However, to date, the mechanisms underlying these aberrant nuclear phenotypes and their biological significance remain poorly understood. Using a model of pancreatic ductal adenocarcinoma (PDAC), the major histological subtypes of pancreatic cancer, we found that oncogenic mutant KRAS reduces nuclear size. Transcriptomic and protein expression analysis of mutant KRAS–expressing PDAC cells revealed differential levels of several nuclear envelope–associated genes. Further analysis demonstrated the nuclear lamina protein, Emerin (EMD), acted downstream of KRAS to mediate nuclear size reduction in PDAC. Analysis of human PDAC samples showed that increased EMD expression associates with reduced nuclear size. Finally, in vivo genetic depletion of EMD in a mutant KRAS–driven PDAC model resulted in increased nuclear size and a reduced incidence of poorly differentiated PDAC. Thus, our data provide evidence of a potentially novel mechanism underlying nuclear size regulation and its effect in PDAC carcinogenesis.

Pancreatic cancer is a malignancy arising from the endocrine or exocrine compartment of this organ. Tumors from exocrine origin comprise over 90% of all pancreatic cancers diagnosed. Of these, pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype. The five-year survival rate for PDAC ranged between 5 and 9% for over four decades, and only recently saw a modest increase to ∼12–13%, making this a severe and lethal disease. Like other cancers, PDAC initiation stems from genetic changes. However, therapeutic targeting of PDAC genetic drivers has remained relatively unsuccessful, thus the focus in recent years has expanded to the non-genetic factors underlying the disease pathogenesis. Specifically, it has been proposed that dynamic changes in the epigenetic landscape promote tumor growth and metastasis. Emphasis has been given to the re-organization of enhancers, essential regulatory elements controlling oncogenic gene expression, commonly marked my histone 3 lysine 4 monomethylation (H3K4me1). H3K4me1 is typically deposited by histone lysine methyltransferases (KMTs). While well characterized as oncogenes in other cancer types, recent work has expanded the role of KMTs as tumor suppressor in pancreatic cancer. Here, we review the role and translational significance for PDAC development and therapeutics of KMTs.

Abstract Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth–promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.