Ductal activation of oncogenic KRAS alone induces sarcomatoid phenotype.
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 KRAS(G12V), 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 KRAS(G12V) 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-KRas(G12V);Ela-CreERT transgenic mice could serve as a useful preclinical model for investigating underlying mechanisms and developing potential therapies.
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Yong
Y
Fu
Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, Texas 77054, USA.
Zobeida
Z
Cruz-Monserrate
Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
H
H
Helen Lin
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Yiyin
Y
Chung
Mayo Clinic, Rochester, Minnesota.
Baoan
B
Ji
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Szu-Min
SM
Lin
Shared Research Animal Resources, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Steven
S
Vonderfecht
Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, Texas 77054, USA.
Craig D
CD
Logsdon
Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
Chien-Feng
CF
Li
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.|Irell &Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
David K
DK
Ann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D000068818:Cetuximab / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D018987:Salivary Ducts / Q000473:pathology*; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000473:pathology*; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013363:Submandibular Gland / Q000473:pathology
C117307:KRAS protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab