Kinase D-interacting substrate of 220kda (Kidins220) and deregulated tyrosine kinase receptors in tumourigenic and invasive traits of pancreatic cancer cells

Shankla, Deepa 2026. Kinase D-interacting substrate of 220kda (Kidins220) and deregulated tyrosine kinase receptors in tumourigenic and invasive traits of pancreatic cancer cells. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Kidins220 (ARMS) is a multi-domain scaffold protein that integrates signals from neurotrophin receptors, receptor tyrosine kinases including EGFR, HER2, IGFIR and PDGFRβ, and Eph receptors. Previous work from our laboratory demonstrated that Kidins220 expression is reduced in pancreatic cancer tissue compared with adjacent non malignant pancreatic tissue, and that this reduction correlates with increased tumour progression through enhanced EGFR/ERK signalling (Cai et al., 2021). These findings suggest that Kidins220 may act as a tumour suppressor in the pancreas, potentially by attenuating oncogenic RTK signalling. Based on these observations, we hypothesise that loss or deregulation of Kidins220 contributes to pancreatic cancer progression by altering receptor tyrosine kinase signalling and interactions with candidate binding partners such as OLFM1. Kidins220 knockdown resulted in the upregulation of IGF-1R and HER2 at both the transcript and protein levels, while EGFR expression increased exclusively at the protein level across all three pancreatic cancer cell lines examined. Analysis of the TCGA-PAAD cohort demonstrated significant inverse correlations between Kidins220 expression and both HER2 and IGF-1R. Moreover, patients exhibiting a Kidins220-low/HER2-high expression profile experienced significantly poorer early overall survival. Functionally, increased IGF-1R expression following Kidins220 knockdown promoted activation of MAPK (ERK, p38, and JNK) and PI3K/AKT signalling pathways in a cell line-dependent manner. Stimulation with IGF-1 induced rapid phosphorylation of IGF-1R within five minutes, an effect that was abolished by the selective IGF-1R inhibitor picropodophyllin (PPP). Kidins220 knockdown significantly enhanced Matrigel invasion, which was markedly attenuated by PPP treatment, particularly in MiaPaCa-2 cells. MMP1 expression was transcriptionally induced following Kidins220 loss and was modulated by IGF-1R inhibition. However, combined inhibition of EGFR and IGF-1R failed to suppress the invasive phenotype completely, suggesting persistent signalling through constitutively activated KRAS pathways. Transcriptomic profiling revealed extensive gene expression alterations following Kidins220 knockdown, with 5,643 and 3,041 differentially expressed genes identified in PANC-1 and MiaPaCa-2 cells. Pathway enrichment analyses implicated aberrant RTK/EGFR signalling. Proteomic analysis encompassing 4,971 proteins corroborated these transcriptomic findings. Among commonly upregulated genes, HSP90AA1 was the highest-ranked candidate. Pharmacological inhibition of HSP90 with NVP-AUY922 reduced EGFR protein abundance and suppressed Matrigel invasion to near-baseline levels, effectively overriding the pro-invasive effects induced by Kidins220 loss. Consistent with these observations, HSP90AA1 expression was significantly elevated in tumour tissues relative to normal pancreas across the TCGA-PAAD, GSE71729, and GSE15471 cohorts, and increased progressively with tumour stage, as assessed by tissue microarray immunohistochemistry. High co-expression of HSP90AA1 and EGFR was associated with significantly poorer overall survival. Notably, OLFM1 was consistently downregulated in pancreatic cancer across three independent patient cohorts. OLFM1 expression was inversely correlated with MMP family members and markers of proliferation, including Ki67 and PCNA. High OLFM1 expression independently predicted improved overall survival and relapsefree survival. In vitro, OLFM1 overexpression suppressed cellular proliferation and demonstrated a trend towards enhanced cell-matrix adhesion. Furthermore, a modest positive correlation between OLFM1 and Kidins220 expression was observed in the TCGA-PAAD cohort, supporting the hypothesis that OLFM1 might have played a role as a novel tumour suppressor downstream of Kidins220 in pancreatic cancer. Taken together, Kidins220 is a multi-RTK tumour suppressor in pancreatic cancer, constraining EGFR, IGF-1R, and HER2 through distinct mechanisms. IGF-1R is a secondary oncogenic RTK activated upon Kidins220 loss. Integrated omics identify HSP90AA1, cell cycle effectors, metabolic reprogramming, and immune evasion as downstream consequences of Kidins220 loss. A Kidins220/ HSP90AA1/ EGFR axis is pharmacologically tractable; HSP90AA1 inhibition suppresses invasion. These findings suggest that OLFM1 may have a potential cosuppressive role alongside Kidins220 in pancreatic cancer, warranting further mechanistic investigation.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	26 October 2026
Last Modified:	26 Oct 2026 09:23
URI:	https://orca.cardiff.ac.uk/id/eprint/190396

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