Abstract 798: Id1 (Inhibitor of differentiation-1) expression demonstrates important translational implications for pancreatic adenocarcinoma

Abstract

Abstract Introduction: Inhibitor of differentiation-1 (Id1) demonstrates a role in tumor progression in a variety of tumors but scarce data exists for pancreatic adenocarcinoma. Previously, we demonstrated that nicotine, the addicting component of tobacco, induces Id1 expression through a Src-dependent signaling pathway promoting proliferation, invasion, and chemoresistance in pancreatic cancer cells. Conversely, silencing of Id1 re-establishes gemcitabine sensitivity in acquired and innate gemcitabine-resistant cell lines. Therefore, we determined the role of Id1 in tumor progression and chemoresistance in vivo and determined the expression status of Id1 in a large cohort of human pancreatic cancer tissues. Methods: Cell lysate analyses (protein analyses, mRNA expression) were determined in a bio-diverse sample of pancreatic cancer cells by western and RT-PCR. Metastatic pancreatic cancer cells were stably transfected with a luciferase expression vector and stable short-hairpin RNA silencing of Id1 gene expression with controls. Orthotopic nude mouse model utilized intraperitoneal injections of nicotine (1mg/kg, M/W/F) and gemcitabine (250 mg/kg, T/Th) with monitoring of in vivo growth and metastases based on luminescent signal concentration. Confirmation of primary tumor and metastases was confirmed by H&E staining. Tissue microarrays (TMAs) constructed from 100 resected pancreatic adenocarcinoma were stained for Id1, phospho-Src, and total Src using immunohistochemistry techniques. Scores based on intensity, percent of positive cells, and pathological grade (1-4) were assigned to each malignant core. Results: In vivo, nicotine significantly promoted tumor growth and metastases in vivo. While gemcitabine reduced the tumor burden in control mice, nicotine abrogates this inhibitory effect. Additionally, knockdown of Id1 results in a significant decrease in tumor burden with no identifiable liver metastases, regardless of nicotine exposure. Analyses of resected pancreatic tumor TMAs demonstrated a statistically significant correlation between Id1 and tumor grade/differentiation (p =0.0368). The correlation of protein levels of Id1 and phospho-Src was also statistically significant (p =0.0024); Comparison of overall survival and tumor grade was also significant (p = 0.05); the correlation between overall-survival and Id1 expression trended toward statistical significance (p =0.06). Conclusions: Id1, through a Src-dependent-Id1 signaling axis, promotes tumorigenesis and chemoresistance in an in vivo pancreatic cancer model. Id1 expression correlates with phospho-Src levels and tumor differentiation in human pancreatic cancer tissues. These results support the clinical assessment of Id1 expression as a biomarker of prognosis and support investigations toward targeted therapies against Id1 for pancreatic cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 798. doi:1538-7445.AM2012-798