Significance of Trask protein interactions in brain metastatic cohorts of lung cancers

Abstract

A class of adhesion protein that occurs in the membrane with both extracellular and intracellular domain and play vital role in maintaining multicellularity is TRASK, also called CUB-domain containing protein1, CD318 (CDCP1). Specifically, in the current study, documented aggressive grades of lung cancers and distant metastatic tissues were examined for protein interactions of Trask and compared with lung cancer variants in situ. The intracellular domain of Trask has the ability to undergo tyrosine phosphorylation and thereafter undergo increased genomic expression, as well as interact with cytoskeletal proteins in the cell periphery and other local signal transduction machinery to induce invadopodia formation and distant metastasis. We incorporated proximity ligation assay to examine protein interactions of Trask in metastatic lung cancer tissues and compare with advanced and low-grade lung cancers restricted to the primary site of origins. Here, we provide direct evidence that activated Trask, which is a phosphorylated form, binds with cytoskeletal proteins actin and spectrin. These interactions were not seen in locally growing lung cancer and cancer in situ. These interactions may be responsible for invadopodia formation and breaking free from a multicellular environment. Functional studies demonstrated interaction between Trask and the STOCs Orai1 and Stim1. Calcium release from internal stores was highest in metastatic lung cancers, suggesting this mechanism as an initial stimulus for the cells to respond chaotically to external growth factor stimulation, especially in aggressive metastatic variants of lung cancers. Recently, inhibitors of STOCs have been identified, and preclinical evidence may be obtained whether these drugs may be of benefit in preventing the deadly consequences of lung cancer.

Mechanistic insights into CDCP1 clustering on non-small-cell lung cancer membranes revealed by super-resolution fluorescent imaging

“…CDCP1, a single-channel transmembrane protein, 4 is overexpressed in NSCLC and is significantly associated with poor prognosis in patients. 5 , 6 , 7 , 8 In malignant tumor cells, CDCP1 can be activated by Src kinase, which promotes the proliferation, invasion, and metastasis of tumor cells through classic signaling pathways such as MAPK (Ras/ERK) and PI3K/AKT. 9 , 10 , 11 , 12 , 13 Besides, numerous studies have demonstrated that antibodies targeting CDCP1, including MAB41-2, MAB10-D7, and C20Fc, can inhibit tumor growth and metastasis in various animal models and improve the efficacy of chemotherapy drugs.…”

Proximity assays for sensitive quantification of proteins

“…Interestingly, measuring activated forms of Akt by in situ PLA does not correlate with phosphorylated Akt or the Akt isoforms as measured by IHC, suggesting that the isoform-specific PLA assays are providing additional clinically relevant information. PLA is showing similar promise for the molecular dissection of a number of other cancers, including lung [78] , [79] , colorectal [80] and prostate [81] cancers. There are fewer publications describing the use of PEA, but this assay has been used to identify five plasma protein biomarkers associated with colorectal cancer, with three of them additionally found to be discriminators of early-stage cancer [55] .…”

Manipulation of the immune system by non-small cell lung cancer and possible therapeutic interference

“…Macrophages can induce angiogenesis, prepare and modulate stroma proteins in favor of invading tumor cells, thus promoting tumor growth, invasion, and metastasis [58,59] . On the contrary, M1 macrophages might inhibit tumor progression not only in the early phase but also during metastasis formation [60,61] . There are additional pathways by which tumor cells can influence the differentiation of M0-macrophages into M2 lineage.…”