ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1)

Abstract

Devil Facial Tumour 1 (DFT1) is one of two transmissible neoplasms of Tasmanian devils (Sarcophilus harrisii) predominantly affecting their facial regions. DFT1's cellular origin is that of Schwann cell lineage where lesions are evident macroscopically late in the disease. Conversely, the pre-clinical timeframe from cellular transmission to appearance of DFT1 remains uncertain demonstrating the importance of an effective pre-clinical biomarker. We show that ERBB3, a marker expressed normally by the developing neural crest and Schwann cells, is immunohistohemically expressed by DFT1, therefore the potential of ERBB3 as a biomarker was explored. Under the hypothesis that serum ERBB3 levels may increase as DFT1 invades local and distant tissues our pilot study determined serum ERBB3 levels in normal Tasmanian devils and Tasmanian devils with DFT1. Compared to the baseline serum ERBB3 levels in unaffected Tasmanian devils, Tasmanian devils with DFT1 showed significant elevation of serum ERBB3 levels. Interestingly Tasmanian devils with cutaneous lymphoma (CL) also showed elevation of serum ERBB3 levels when compared to the baseline serum levels of Tasmanian devils without DFT1. Thus, elevated serum ERBB3 levels in otherwise healthy looking devils could predict possible DFT1 or CL in captive or wild devil populations and would have implications on the management, welfare and survival of Tasmanian devils. ERBB3 is also a therapeutic target and therefore the potential exists to consider modes of administration that may eradicate DFT1 from the wild.

Fig 1. DFT1 staining and skin manifestation.

(A) Haematoxylin and Eosin stained DFT1 x40, (B) ERBB3 Immunohistochemical expression in DFT1 strain 3 x40, (C) ERBB3 immunohistochemical expression in DFT1 strain 3 x100, (D) DFT1 negative control, (E) Tasmanian devil skin and subcutis section with peripheral nerve (red arrow) and DFT1 (black arrow) x10, (F) Tasmanian devil lymph node ERBB3 expression lymphoid follicle x20, (G) Tasmanian devil bowel ERBB3 positive control x40, (H) ERBB3 IHC negative control bowel, (I) trigeminal nerve shows ERBB3 positive nerve body (black arrow) and occasional adaxonal ERBB3 positivity (red arrows) x40, (J) ERBB3 IHC negative control trigeminal nerve, (K) Tasmanian Devil gross appearance of DFT1. Photo credit: DPIPWE archive, (L) Tasmanian devil gross appearance cutaneous lymphoma. Photo credit DPIPWE archive.

Fig 2. Serum ERBB3 levels in Tasmanian devils.

Serum ERBB3 levels were measured by ELISA in clinically healthy Tasmanian devils CHD (n = 11), clinically healthy Tasmanian devils with dermatopathy CHDD (n = 4), clinically diagnosed DFT1 (n = 8) and those with cutaneous lymphoma CL (n = 12). Horizontal dashed line indicates the limit of detection of the ELISA assay at 30 pg/mL. Results of individual devils are shown with the median and interquartile range identified by the whiskers. Significance testing using a Kruskal-Wallis test with Dunn’s Multiple Comparison Testing shown with * representing p < 0.05.