Abstract A051: CREB1 integrates EGFR/ERK and p38/LIF oncogenic inputs as a transcriptional convergence hub in pancreatic ductal adenocarcinoma
Rohan Moniruzzaman, Kamalpreet Kaur Sandha, Varunkumar Krishnamoorthy, Nitu Renuka Heggade, Poorva Poorva, Camille Marie Acevedo, Rimpi Khurana, Yuguang Ban, Nipun Merchant, Austin R Dosch, Vineet Kumar Gupta, Nagaraj NagathihalliAbstract
Background.
Pancreatic ductal adenocarcinoma (PDAC) is driven by convergent oncogenic signaling; however, transcriptional regulators that integrate these pathways remain poorly understood. CREB1 is activated via the EGFR/ERK/MSK1 and p38/LIF axes, making it a potential transcriptional convergence node. The CREB1-associated co-expression network and its cell-type-specific activity across the immunosuppressive tumor microenvironment (TME) remain undefined.
Methods.
We integrated multi-cohort transcriptomic datasets from TCGA PAAD, an independent validation cohort, and human PDAC cell lines for comprehensive analysis. To define cell-type-specific CREB1 activity, we expanded our analysis to a single-cell RNA-seq atlas of human PDAC cells across disease stages and evaluated CREB1-associated programs across tumor and stromal populations. Protein level and pathway activation were validated by Western blotting, immunostaining in PDAC cell lines, and patient-derived specimens to confirm CREB1's role in regulating EGFR/ERK and p38/LIF signaling.
Results.
TCGA PAAD analysis revealed significant activation of the CREB1 signaling along with STAT3, with LIF being the most elevated. CREB1 was co-expressed with EP300/p300, followed by upstream kinases ERK2/MAPK1, JAK1, MSK1/RPS6KA5, p38α/MAPK14, as well as downstream effectors EGFR and STAT3. Mechanistically, pharmacologic CREB1 inhibition in PDAC cells significantly increased EGFR phosphorylation while reducing p38 phosphorylation, revealing reciprocal cross-regulation between the two pathway arms. Immunostaining of mouse tumor cell–derived PDAC tumors and patient specimens confirmed concordant CREB1-dependent regulation of both signaling arms. Among CREB1 and EGFR expression subgroups, CREB1-low/EGFR-high subgroup exhibited the worst median overall survival in TCGA PAAD. High CREB1 and low EGFR tumors showed increased LIF and p38β expression with suppressed EREG and AREG, consistent with context-dependent activation of the p38/LIF pathway. The correlation between CREB expression and EGFR status was confirmed in human and mouse PDAC cell lines. Single-cell analysis identified CREB1 enrichment in Tissue-Resident M2 macrophages and regulatory T cells (Tregs), with STAT3 marking the earliest tissue-resident macrophage state. Tregs expanded during tumor progression, while endothelial LIFR expression gradually decreased, indicating dynamic remodeling of LIF-LIFR signaling during PDAC progression.
Conclusions.
CREB1 functions as a context-dependent transcriptional integrator linking EGFR/ERK and p38/LIF oncogenic inputs in PDAC, validated at both the transcriptomic and protein levels. Single-cell analysis reveals CREB1/STAT3 co-activity in immunosuppressive TME populations, while LIF-driven disruption of endothelial LIFR signaling occurs across disease progression. These findings highlight targeting the CREB1 hub, including JAK/STAT3 blockade in immunosuppressive TME populations, and EGFR-directed therapy as strategies based on solid mechanisms.
Citation Format:
Rohan Moniruzzaman, Kamalpreet Kaur Sandha, Varunkumar Krishnamoorthy, Nitu Renuka Heggade, Poorva Poorva, Camille Marie Acevedo, Rimpi Khurana, Yuguang Ban, Nipun Merchant, Austin R Dosch, Vineet Kumar Gupta, Nagaraj Nagathihalli. CREB1 integrates EGFR/ERK and p38/LIF oncogenic inputs as a transcriptional convergence hub in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A051.