SRSF1: Key Player in Pancreatic Ductal Adenocarcinoma Initiation and Progression

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis, often diagnosed at an advanced stage with distant metastases, rendering traditional treatments like surgery and chemotherapy ineffective. The genetic landscape of PDAC is dominated by somatic activating mutations in the KRAS gene, particularly the G12D substitution, which leads to constitutive activation of KRAS signaling pathways. Mouse models have provided insights into how mutant KRAS initiates the transformation of pancreatic cells, resulting in preneoplastic lesions like acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. However, it is clear that additional oncogenic alterations are required for further PDAC progression. Epidemiological studies have suggested a strong association between chronic pancreatitis and the development of PDAC. Although pancreatitis alone may not induce PDAC, it accelerates the tumorigenesis driven by mutant KRAS. Notably, the IL1/IL1R1 pathway, implicated in inflammation, plays a significant role in cancer initiation and progression. IL1 secreted by PDAC cells can promote malignancy through autocrine and paracrine mechanisms. Additionally, the upregulation of IL1R1 is observed in human PDAC tumors, making it a potential target for therapeutic intervention.

Precise regulation of pre-mRNA alternative splicing is a cornerstone of cellular identity and organ development. However, alterations in this process can contribute to tumorigenesis. Until recently, the contribution of aberrant RNA splicing to pancreatitis and PDAC had not been extensively explored. Serine/arginine-rich splicing factor 1 (SRSF1) is involved in RNA splicing and contributes to gene expression regulation and proteome diversity. Dysregulation or mutations of splicing factors like SRSF1 can lead to tumor development by altering pre-mRNA alternative splicing events. While SRSF1’s oncogenic properties are known in various cancers, its role in pancreatitis and PDAC tumorigenesis was previously unknown. Understanding the underlying mechanisms of PDAC initiation and progression is of paramount importance for developing effective prevention and treatment strategies. To this end, recent research published in the peer-reviewed journal Cancer Discovery by a team of scientists from the Cold Spring Harbor Laboratory in New York, composed of Dr. Ledong Wan, Dr. Kuan-Ting Lin, Dr. Mohammad Alinoor Rahman, Dr. Yuma Ishigami, Dr. Zhikai Wang, Dr. Mads Jensen, Dr. John E Wilkinson, Dr. Youngkyu Park, Professor David Tuveson, and Professor Adrian Krainer, investigated the critical roles of SRSF1 and IL1R1 (interleukin-1 receptor 1) in PDAC initiation and progression. The authors demonstrated that SRSF1 is associated with and promotes pancreatitis in mice by increasing MAPK signaling through changes in alternative splicing of IL1R1 mRNA. Interestingly, SRSF1 initially undergoes destabilization as a negative feedback response to KRASG12D mutation, helping maintain pancreatic cell homeostasis. This negative feedback regulation of SRSF1 is overridden by the transcription factor oncogene MYC, which accelerates KRASG12D-mediated PDAC initiation and progression. They observed elevated SRSF1 expression in human PDAC tumors, which is associated with poor prognosis. Knocking down SRSF1 suppresses human PDAC organoid growth and inhibits colony formation and migration in PDAC cell lines. Subcutaneous xenografts in mice also exhibited reduced tumor growth upon SRSF1 knockdown. Furthermore, SRSF1 deficiency in a mouse model perturbs KRASG12D-mediated PDAC initiation, highlighting its crucial role in PDAC development.

The authors generated a mouse model, KSC, in which SRSF1 is inducibly overexpressed in the pancreas, along with KRASG12D. In KSC mice, most pancreatic cells are transformed and exhibit neoplasia, high-grade PanIN lesions, interstitial edema, and collagen deposition, in contrast to the mostly normal pancreata of young KC mice. This indicates that SRSF1 cooperates with KRASG12D to promote tumorigenesis. Additionally, introducing TP53 mutation in KPSC mice accelerated PDAC development, emphasizing the role of SRSF1 in driving KRASG12D-dependent PDAC progression. The study uncovers that SRSF1 promotes MAPK signaling activation, a prerequisite for KRASG12D-mediated pancreas cell transformation and PDAC initiation. This finding is crucial in understanding how SRSF1 contributes to PDAC development and underscores the intricate interplay between different signaling pathways in cancer. The researchers observed that SRSF1 expression decreases in morphologically normal pancreatic cells with active KRASG12D, suggesting the existence of a compensatory feedback mechanism, which they show involves SRSF1 ubiquitination and degradation by the proteasome. This feedback helps maintain intracellular signaling homeostasis and pancreatic cell identity, highlighting the complexity of the molecular events involved in PDAC initiation.

The research team also investigated the role of MYC, a known oncogene often overexpressed in PDAC, in regulating SRSF1 expression. They demonstrated that MYC activation consistently increases SRSF1 expression, likely serving as a direct transcriptional activator of SRSF1. Moreover, negative enrichment of protein ubiquitination pathways upon MYC activation suggests that MYC might act as a cooperating oncogenic partner of KRASG12D in PDAC tumorigenesis in part by suppressing SRSF1 ubiquitination. Furthermore, MYC’s association with metaplasia and inflammation aligns with its potential role in driving PDAC progression.

The authors’ identification of IL1R1 as a splicing target of SRSF1 is a crucial finding. SRSF1 promotes the inclusion of exon 3 in the 5′ UTR of IL1R1 mRNA, enhancing its stability. This results in elevated IL1R1 expression, contributing to the pro-inflammatory environment associated with pancreatitis and PDAC. IL1R1 is confirmed to play a prominent role in SRSF1-induced pancreatitis and transformation, further highlighting its significance in PDAC initiation and progression. The clinical implications of these findings are profound. Ongoing clinical trials evaluating the IL1R1 antagonist Anakinra in combination with standard chemotherapy highlight the potential of targeting IL1 signaling in PDAC treatment. Moreover, SRSF1-regulated splicing changes, including in IL1R1, may serve as promising markers and therapeutic targets for both pancreatitis and PDAC. These findings could open new doors in the development of targeted therapies for these challenging conditions. Furthermore, the study demonstrated that SRSF1 alone is sufficient to increase IL1R1 expression and activate MAPK signaling in ductal organoids, suggesting an intrinsic process. It is noteworthy to mention that SRSF1-induced MAPK signaling activation and pancreatitis can be alleviated by Il1r1 depletion or treatment with the MEK inhibitor trametinib, signifying the crucial role of SRSF1 in promoting pancreatitis through MAPK signaling.

The authors’ findings collectively establish SRSF1 as a key regulator in the cellular homeostasis response to KRASG12D and in KRASG12D-mediated PDAC tumorigenesis. Importantly, SRSF1 levels decrease in normal pancreatic cells expressing KRASG12D as part of a homeostatic response to buffer MAPK signaling. Conversely, elevated SRSF1 disrupts cellular homeostasis, accelerating PDAC initiation and progression. This intricate dance between SRSF1 and KRASG12D unveils a novel layer of complexity in the pathogenesis of PDAC.

The research conducted by Professor Krainer and colleagues at the Cold Spring Harbor Laboratory presents a detailed comprehensive investigation into the roles of SRSF1 and IL1R1 in PDAC initiation and progression. Their findings offer potential therapeutic targets for future research and drug development. Understanding the interplay between splicing factors, signaling pathways, and oncogenes in PDAC is a significant step toward improving the prognosis and treatment options for this deadly cancer.