Abstract
Semaphorin-5A (SEMA5A) has differential cell surface expression between normal and cancer cells and represents an attractive target for therapeutic intervention in pancreatic cancer (PC). In this study, we delineated the pathological expression and significance of SEMA5A during PC progression and metastasis. We utilized human tissue microarrays and different PC mouse models (Pdx1-cre; LSL- Kras(G12D), Pdx1-Cre; LSL-Kras(G12D); LSL-p53(R172H) and RIP1-Tag2) to analyze SEMA5A expression during PC progression. Using human patients and different mouse models, we demonstrated that SEMA5A expression was highest in liver metastases, followed by primary pancreatic tumors, and the lowest expression was found in the normal pancreas. SEMA5A expression was localized on tumor cells with no staining in the surrounding stroma. To understand the functional significance of SEMA5A, we treated PC cell lines with recombinant SEMA5A. We observed an increase in migration, chemotaxis, and scattering of PC cells. To delineate the signaling axis of SEMA5A, we generated SEMA5A receptor-Plexin-B3 knockdown in T3M-4 and CD18/HPAF PC cell lines and observed that the effect of SEMA5A treatment was absent in the Plexin-B3 knockdown counterparts of T3M-4 and CD18/HPAF cells. SEMA5A treatment leads to phosphorylation of cMET in Plexin-B3 dependent manner. Our data demonstrate that there is an increase in SEMA5A expression during PC progression and the elevation of this expression takes place at metastatic sites especially the liver in both exocrine and endocrine tumors. SEMA5A can elicit a migratory response in cells by activating cMET through the Plexin-B3 receptor. In conclusion, SEMA5A signaling represents a potential molecule for targeting metastasis in pancreatic cancer.
Highlights
Semaphorins are well known for their function as guidance and migration cue molecules designed to help cell reach the target site during embryonic development of the nervous system and cardiovascular patterning [1,2,3]
We determined the prospects of SEMA5A as a potential therapeutic target for pancreatic cancer (PC) by analyzing the pattern of SEMA5A expression in both human and murine PC tissues of the primary tumor as well as metastasis, and normal pancreas and its functional role in PC
We took advantage of KC and KPC mouse models for studying SEMA5A expression in PDAC and RT2 model of islet-cell carcinoma for PanNET. These mouse models of PC provide information about the progression of PC [29], but both KC and KPC models bear a striking similarity to the PDAC condition [30] and KPC model recapitulate histopathologic condition of metastasis to relevant sites
Summary
Semaphorins are well known for their function as guidance and migration cue molecules designed to help cell reach the target site during embryonic development of the nervous system and cardiovascular patterning [1,2,3]. SEMA5A has not been associated with a univocal role in cancer [17], as it acts as a tumor promoter in cancers like gastric [14,15,16], prostate [20] and, ovary [23] while it acts as a tumor suppressor in glioma [11, 12] and lung cancer [13] This contradictory functions of this molecule can be attributed to the possible interaction of SEMA5A with different receptors and thereby activation of divergent pathways in a tissuespecific manner [17]. The variable response of SEMA5A towards differences in extracellular matrix components of different tissues [24] can be a potential reason as the molecule itself has bifunctionality due to presence of two opposing domains (Sema and Thrombospondin)
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