Ductal activation of oncogenic KRAS alone induces sarcomatoid phenotype.

Yong Fu,Steven Vonderfecht,Zobeida Cruz-Monserrate,David K Ann,H Helen Lin,Baoan Ji,Craig D Logsdon,Chien-Feng Li,Szu-Min Lin,Yiyin Chung

doi:10.1038/srep13347

Abstract

Salivary duct carcinoma (SDC) is an uncommon, but aggressive malignant tumor with a high mortality rate. Herein, we reported the detection of somatic KRAS A146T and Q61H mutations in 2 out of 4 (50%) sarcomatoid SDC variants. Transgenic mice carrying the human oncogenic KRASG12V, which spatiotemporal activation by tamoxifen (TAM)-inducible Cre recombinase Ela-CreERT in the submandibular gland (SMG) ductal cells, was established and characterized. Visible carcinoma was detected as early as day-15 following oncogenic KRASG12V induction alone, and these tumors proliferate rapidly with a median survival of 28-days accompanied with histological reminiscences to human sarcomatoid SDC variants. Moreover, these tumors were resistant to cetuximab treatment despite augmented EGFR signaling, attesting its malignancy. Our findings suggest that LGL-KRasG12V;Ela-CreERT transgenic mice could serve as a useful preclinical model for investigating underlying mechanisms and developing potential therapies.

Highlights

Human salivary duct carcinoma (SDC) is a highly aggressive adenocarcinoma of salivary glands
To identify the genetic mutation that contributed to the pathogenesis of Salivary duct carcinoma (SDC), one of the most aggressive subtypes of salivary gland cancers, we investigated 18 SDC biospecimens to search for either somatic KRas or epidermal growth factor receptor (EGFR) mutation
We have identified oncogenic KRAS mutation in human sarcomatoid SDCs and further generated and characterized a conditional inducible transgenic mouse model, LGL-KRasG12V;Elastase I (Ela)-CreERT, to demonstrate the associated pathological manifestations

Summary

Introduction

Human salivary duct carcinoma (SDC) is a highly aggressive adenocarcinoma of salivary glands. The use of combinations of lesions might reveal synergistic effects or dependencies of two genetic lesions, the use of multiple mutations substantially complicates the interpretation To address this unmet need for a SDC animal model and to examine the role of oncogenic KRAS mutation in SDC pathogenesis, we have established a novel mouse model (LGL-KRasG12V;Ela-CreERT). The mouse model uses the SMG ductal cell-specific Elastase I (Ela) promoter to drive expression of a tamoxifen (TAM)-inducible form of Cre recombinase (CreERT). We found that tumor cells originated from a subpopulation of cells at the abluminal region of the granulated convoluted tubules (GCTs) and striated ducts To our knowledge, this animal model is the first one with a defined ductal origin of salivary gland malignancy. Our LGL-KRasG12V;Ela-CreERT mouse model is a step forward due to its ductal cell specificity, high tumor incidence, and rapid onset

Methods

Results

Conclusion