Loss of EGFR-ASAP1 signaling in metastatic and unresectable hepatoblastoma

Abstract

Hepatoblastoma (HBL), the most common childhood liver cancer is cured with surgical resection after chemotherapy or with liver transplantation if local invasion and multifocality preclude resection. However, variable survival rates of 60–80% and debilitating chemotherapy sequelae argue for more informed treatment selection, which is not possible by grading the Wnt-β-catenin over activity present in most HBL tumors. A hypothesis-generating whole transcriptome analysis shows that HBL tumors removed at transplantation are enriched most for cancer signaling pathways which depend predominantly on epidermal growth factor (EGF) signaling, and to a lesser extent, on aberrant Wnt-β-catenin signaling. We therefore evaluated whether EGFR, ASAP1, ERBB2 and ERBB4, which signal downstream after ligation of EGF, and which show aberrant expression in several other invasive cancers, would also predict HBL tumor invasiveness. Immunohistochemistry of HBL tumors (n = 60), which are histologically heterogeneous, shows that compared with well-differentiated fetal cells, less differentiated embryonal and undifferentiated small cells (SCU) progressively lose EGFR and ASAP1 expression. This trend is exaggerated in unresectable, locally invasive or metastatic tumors, in which embryonal tumor cells are EGFR-negative, while SCU cells are EGFR-negative and ASAP1-negative. Loss of EGFR-ASAP1 signaling characterizes undifferentiated and invasive HBL. EGFR-expressing HBL tumors present novel therapeutic targeting opportunities.

The presence of PIM3 increases hepatoblastoma tumorigenesis and tumor initiating cell phenotype and is associated with decreased patient survival

“…Li et al demonstrated that PIM3 induced stemness via activation of the STAT3 pathway [23]. The STAT3 pathway has not been studied in hepatoblastoma aside from the understanding that STAT3 signaling is present [24,25]. Additionally, many of the pathways through which we have already demonstrated PIM3 to play a role in hepatoblastoma tumorigenicity are related to characteristics of SCLCCs.…”

Volasertib preclinical activity in high-risk hepatoblastoma

“…PLK3 a, b refer to different Affymetrix probes. (C) mRNA expression data from Ranganathan, et al [23]. Fold change was found to be statistically significantly different from a hypothetical value of 1 by student’s t -test, p =0.0024.…”

“…In another study, RNA expression was analyzed by microarray from tumor (n=25) and normal (n=4) [22]. A third study performed RNA sequencing for tumor (n=10) and normal (n=3) [23]. In all three sets of data, PLK1 was overexpressed (absolute mean expression 1.51 TPM ± 0.25 SEM, 6.49±0.13 and 1.95±0.36, respectively) with 1.9±0.28 average fold change between tumor and normal (Figure 2A) from the first study, with 1.05± 0.02 fold change (Figure 2B) from the second study and 4.19±0.08 fold change from the third study (Figure 2C).…”

Identification of differentially expressed genes, lncRNAs and miRNAs which are associated with tumor malignant phenotypes in hepatoblastoma patients

“…In this conducted network, we identified two genes in epidermal growth factor (EGF) signaling, EGFR and SDC1 [ 40 ], acting as effector genes. Recently, a whole transcriptome analysis based on HB patients suggested that aberrant EGF signaling was associated with HB classification [ 41 ]. The loss of EGFR signaling members were shown to be more present in less differentiated embryonal and undifferentiated small cells subtypes of HB.…”