Transcriptional background effects on a tumor driver gene in different pigment cell types of medaka

Abstract

The Xiphophorus melanoma receptor kinase gene, xmrk, is a bona fide oncogene driving melanocyte tumorigenesis of Xiphophorus fish. When ectopically expressed in medaka, it not only induces development of several pigment cell tumor types in different strains of medaka but also induces different tumor types within the same animal, suggesting its oncogenic activity has a transcriptomic background effect. Although the central pathways that xmrk utilizes to lead to melanomagenesis are well documented, genes and genetic pathways that modulate the oncogenic effect and alter the course of disease have not been studied so far. To understand how the genetic networks between different histocytes of xmrk‐driven tumors are composed, we isolated two types of tumors, melanoma and xanthoerythrophoroma, from the same xmrk transgenic medaka individuals, established the transcriptional profiles of both xmrk‐driven tumors, and compared (1) genes that are co‐expressed with xmrk in both tumor types, and (2) differentially expressed genes and their associated molecular functions, between the two tumor types. Transcriptomic comparisons between the two tumor types show melanoma and xanthoerythrophoroma are characterized by transcriptional features representing varied functions, indicating distinct molecular interactions between the driving oncogene and the cell‐type‐specific transcriptomes. Melanoma tumors exhibit gene signatures that are relevant to proliferation and invasion, while xanthoerythrophoroma tumors are characterized by expression profiles related to metabolism and DNA repair. We conclude the transcriptomic backgrounds, exemplified by cell‐type‐specific genes that are downstream of xmrk effected signaling pathways, contribute the potential to change the course of tumor development and may affect overall tumor outcomes.

Segregation between an ornamental and a disease driver gene provides insights into pigment cell regulation

“…Mpileup files were made using legend version of samtools (v0. 19) and genotyping was processed using Bcftools. Genotype in this study refers to inheritance of ancestral alleles, with heterozygous meaning that a locus exhibited genetic material from both ancestors (i.e., X. maculatus and X. couchianus), and homozygous means that a locus exhibited genetic material from only the one parental species.…”

“…Even so, the xanthophore tumor (i.e., xanthophoroma) only develops as epiphytic nodules without invasion. Xanthophoroma gene expression profile suggests it is less proliferative and less invasive than the melanoma counterpart (18, 19). The absence of the xmrk effect in xanthophores in Xiphophorus hybrids implies that despite Sd and Dr being linked yet are subjected to different regulation.…”