The putative tumor suppressor geneEphA3fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis

Abstract

Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wild-type lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis.

CCR10+ epithelial cells from idiopathic pulmonary fibrosis lungs drive remodeling

“…Sixty-three days after administration, the number of CCR10 + epithelial cells from IPF, but not normal, lungs correlated with hydroxyproline concentration in fibrotic humanized NSG lung tissues. Consistent with the expression of various mesenchymal markers by single-cell RNA-sequenced CCR10 + epithelial cells, flow cytometric analysis showed that these cells in IPF lungs highly express the receptor tyrosine kinase EphA3, which has been previously reported to be enriched on mesenchymal cells in developing murine lungs (33). Further, a subset of epithelial cells that highly express CCR10 and EphA3 proteins more consistently induced lung remodeling in humanized mice relative to epithelial cells from the same patient expressing low levels of CCR10 transcript and no EphA3 protein.…”

“…We have recently shown that a subset of CCR10 + structural cells coexpress the receptor tyrosine kinase EphA3 (ref. 18 and manuscript in revision), a putative pulmonary mesenchymal marker (33). Given the expression of a few mesenchymal markers in single-cell RNA-sequenced KRT5 + CCR10 + epithelial cells (as shown in Figure 5, E and F), the expression of EphA3 on CCR10 + epithelial cells was assessed.…”

A panel of protein kinase high expression is associated with postoperative recurrence in cholangiocarcinoma

“…Eph receptor is another receptor tyrosine kinase which has been studied in CCA. The interaction of Eph receptor and ephrin ligand associated with the modification of actin cytoskeleton, adhesion, as well as cell shape [31]. In addition, upregulation of EhpA3 has also been reported to associate with tumor metastasis and recurrence in gastric cancer [32].…”

EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway

“…With respect to its putative role in tumorigenesis, previous studies have indicated that EPHA3 can signal both in a kinase-dependent and kinase-independent manner, inducing both tumor-promoting and tumor-suppressing effects [42, 43]. In glioblastoma multiforme, EPHA3 has exhibited highly expression in undifferentiated mesenchymal cells and has been especially assigned a kinase-independent oncogenic role based on its modulating mitogen-activated protein kinase (MAPK) signaling [15].…”

“…However, in a series of studies of non-small cell lung cancer (NSCLC), EPHA3 was identified as a tumor suppressor with decreased expression levels. The reduction in receptor activity conferred by the point mutations of EPHA3 found in cancers, and ligand- and EPHA3-dependent apoptosis of tumor and stroma cells upon receptor agonist treatment suggested that wild-type EPHA3 has anti-tumorigenic properties in NSCLC [19, 43–46]. …”