Comprehensive Genomic Profiling of Patient-matched Head and Neck Cancer Cells: A Preclinical Pipeline for Metastatic and Recurrent Disease.

Nisa, Lluís; Barras, David; Medova, Michaela; Aebersold, Daniel M.; Medo, Matúš; Poliaková, Michaela; Koch, Jonas; Bojaxhiu, Beat; Eliçin, Olgun; Dettmer, Matthias S.; Angelino, Paolo; Giger, Roland; Borner, Urs; Caversaccio, Marco D.; Carey, Thomas E; Ho, Liza; McKee, Thomas A; Delorenzi, Mauro; Zimmer, Yitzhak (2018). Comprehensive Genomic Profiling of Patient-matched Head and Neck Cancer Cells: A Preclinical Pipeline for Metastatic and Recurrent Disease. Molecular cancer research, 16(12), pp. 1912-1926. American Association for Cancer Research AACR 10.1158/1541-7786.MCR-18-0056

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Metastases and tumor recurrence have a major prognostic impact in head and neck squamous cell carcinoma (HNSCC); however, cellular models that comprehensively characterize metastatic and recurrent HNSCC are lacking. To this end, we obtained genomic, transcriptomic, and copy number profiles of the UM-SCC cell line panel, encompassing patient-matched metastatic and recurrent cells. UM-SCC cells recapitulate the most prevalent genomic alterations described in HNSCC, featuring common TP53, PI3K, NOTCH, and Hippo pathway mutations. This analysis identified a novel F977Y kinase domain PIK3CA mutation exclusively present in a recurrent cell line (UM-SCC14B), potentially conferring resistance to PI3K inhibitors. Small proline-rich protein 2A (SPRR2A), a protein involved in epithelial homeostasis and invasion, was one of the most consistently downregulated transcripts in metastatic and recurrent UM-SCC cells. Assessment of SPRR2A protein expression in a clinical cohort of patients with HNSCC confirmed common SPRR2A downregulation in primary tumors (61.9% of cases) and lymph node metastases (31.3%), but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy (HR 2.81; 95% CI, 1.16-6.79; = 0.02). These results suggest that SPRR2A plays a dual role in invasion and therapeutic resistance in HNSCC, respectively through its downregulation and overexpression. The current study reveals translationally relevant mechanisms underlying metastasis and recurrence in HNSCC and represents an adjuvant tool for preclinical research in this disease setting. Underlining its discovery potential this approach identified a PIK3CA-resistant mutation as well as SPRR2A as possible theragnostic markers.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Nisa Hernández, Lluís; Medova, Michaela; Aebersold, Daniel; Medo, Matúš; Poliaková, Michaela; Koch, Jonas Paul; Bojaxhiu, Beat; Eliçin, Olgun; Dettmer, Matthias; Giger, Roland; Borner, Urs; Caversaccio, Marco and Zimmer, Yitzhak

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1541-7786

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

07 Nov 2018 10:26

Last Modified:

05 Dec 2018 01:32

Publisher DOI:

10.1158/1541-7786.MCR-18-0056

PubMed ID:

30108165

URI:

https://boris.unibe.ch/id/eprint/120957

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