Prognostic Relevance of CCDC88C (Daple) Transcripts in the Peripheral Blood of Patients with Cutaneous Melanoma

“…Our findings also shed light into the two seemingly opposite ways in which Daple influences cancer initiation and progression; it acts as tumor suppressor in the normal epithelium and during early stages while supporting EMT/ invasion during late stages (Aznar et al, 2015;Dunkel et al, 2018). This bifaceted role is shared by two other prominent signaling pathways-TGF-b and the non-canonical b-catenin-independent signaling that is triggered by Wnt5A/FZD7 (Akhurst and Derynck, 2001;McDonald and Silver, 2009).…”

“…We also demonstrate how growth factors may shape these scaffolding functions of Daple via their ability to trigger two key tyrosine phosphoevents targeting Daple's PBM. These phosphoevents dictate the localization of Daple, as well as its interactome: Daple that is not phosphorylated or hypophosphorylated (i.e., only on one tyrosine) may bind PARD3 and localize to the junctions, however, Daple that is hyperphosphorylated (i.e., on both tyrosines) may not bind either; instead, it localizes to the cytoplasm and may continue to modulate G protein signaling downstream of Our findings also shed light into the two seemingly opposite ways in which Daple influences cancer initiation and progression; it acts as tumor suppressor in the normal epithelium and during early stages and supports EMT/invasion during late stages [9,37]. This bi-faceted role is shared by two other prominent signaling pathways-TGFβ and the non-canonical β-cateninindependent signaling that is triggered by Wnt5A/FZD7 [38,39].…”

“…This is because we and others have shown that transcriptional upregulation or post-transcriptional activation [41][42][43] of GIV (the 'linker' between the two GTPases; Figure 1A) supports several aggressive tumor cell properties, including, proliferation, invasiveness, stemness, survival, chemoresistance and angiogenesis 25,44 . Consistent with the notion that cell autonomy fuels unrestricted proliferation 2 , collective invasiveness [45][46][47][48] , and adaptability (drug resistance 49 ), elevated expression of the GIV linker protein in a variety of solid tumors 29,44 , both in primary tumors 50,51 as well as in circulating tumor cells 52,53 have been shown to correlate with tumor aggressiveness and poor survival across cancers. Finally, model and PPI network-driven predictions of uncoupling the GTPases or interrupting secrete-and-sense autonomy were experimentally validated in the two cancer cell lines in the absence of the GIV linker protein (Figure 1D).…”

“…Our choice was guided by two reasons: ( i ) HeLa cells not only represent the most robust system to study Golgi structure (Ayala and Colanzi, 2016; Wortzel et al, 2017) and function (Rauter et al, 2020), but also provide continuity with prior work because all biophysical and functional studies that led to the discovery of the coupled GTPases at the Golgi were performed in this model; ( ii ) we and others have shown that transcriptional upregulation or post-transcriptional activation (Bhandari et al, 2015; Dunkel et al, 2012; Sasaki et al, 2015) of GIV (the ‘linker’ between the two GTPases; Figure 1A ) supports several aggressive tumor cell properties (of which, many were demonstrated in MDA-MB231 cells (Jiang et al, 2008; Lopez-Sanchez et al, 2015; Midde et al, 2018; Rahman-Zaman et al, 2018; Rohena et al, 2020; Wang et al, 2015; Wang et al, 2017)), including, invasion, matrix degradation, proliferation and survival (Aznar et al, 2016; Garcia-Marcos et al, 2015). Elevated expression of GIV has also been reported in a variety of solid tumors (Garcia-Marcos et al, 2015; Getz et al, 2019), both in primary tumors (Ghosh, 2015; Ghosh et al, 2016b) as well as in circulating tumor cells (Barbazan et al, 2016; Dunkel et al, 2018) have been shown to correlate with tumor aggressiveness and poor survival across cancers. Finally, model and PPI network-driven predictions of uncoupling the GTPases or interrupting secrete-and-sense autonomy were experimentally validated in the two cancer cell lines that lack GTPase coupling in the absence of the GIV linker protein.…”