Distinct Origin of Claudin7 in Early Tumor Endosomes Affects Exosome Assembly

Abstract

Microvesicles are the body's most powerful intercellular communication system and cancer-initiating cell microvesicles (CIC-TEX) reprogram Non-CIC towards fortified malignancy. Claudin7, a CIC-biomarker in gastrointestinal tumors, is recovered in TEX. Recent evidence suggesting individual cells delivering distinct microvesicles became of particular interest for claudin7, which is part of tight junctions (TJ) and glycolipid-enriched membrane domains (GEM), GEM-located claudin7 is palmitoylated. This offered the unique possibility of exploring the contribution of a CIC marker and its origin from distinct membrane domains on CIC-TEX biogenesis and activities. Proteome and miRNA analysis of wild-type, claudin7-knockdown and a rescue with claudin7 harboring a mutated palmitoylation site (mP) of a rat pancreatic and a human colon cancer line uncovered significant, only partly overlapping contributions of palmitoylated and non-palmitoylated claudin7 to TEX composition. Palmitoylated claudin7 facilitates GEM-integrated plasma membrane and associated signaling molecule recruitment; non-palmitoylated claudin7 supports recruitment of trafficking components, proteins engaged in fatty acid metabolism and TJ proteins into TEX. Claudin7mP also assists TEX recovery of selected miRNA. Thus, distinctly located claudin7 affects CIC-TEX composition and TJ-derived cld7 might play a unique role in equipping CIC-TEX with transporters and lipid metabolism-regulating molecules, awareness of distinct TEX populations being crucial facing therapeutic translation.

Exosomal Components and Modulators in Colorectal Cancer: Novel Diagnosis and Prognosis Biomarkers

“…Chiba recruited exosomes from SW480 cells (GSE68979), and Ji et al distinguished three subtypes of EVs from the human LIM1863 cancer cell line [131]. Moreover, Sun and his group reported their results in HT-29 and SW-948 cells [134,135]. Some stem cell markers (CD44v6, Tspan8, CD151, and Claudin7) have been manipulated in exosome research.…”

The potential roles of exosomes in pancreatic cancer initiation and metastasis

“…It has also been shown that Cld7 can be distributed beyond TJ sites. For instance, palmitoylated Cld7 (Palm-Cld7) is localized in glycolipid-enriched membrane microdomains (GEMM) [ 113 ]. Cld7 in tight junction (TJ-Cld7) is shown to regulate the entry of related proteins into PaCaExos and affect the function of exosomes derived from CICs (CIC-Exos) by modulating the composition of exosomal transporters and lipid metabolites, while Palm-Cld7-positive exosomes have the capability of regulating cell migration [ 113 ].…”

“…For instance, palmitoylated Cld7 (Palm-Cld7) is localized in glycolipid-enriched membrane microdomains (GEMM) [ 113 ]. Cld7 in tight junction (TJ-Cld7) is shown to regulate the entry of related proteins into PaCaExos and affect the function of exosomes derived from CICs (CIC-Exos) by modulating the composition of exosomal transporters and lipid metabolites, while Palm-Cld7-positive exosomes have the capability of regulating cell migration [ 113 ]. Importantly, Kyuno and colleagues have found that murine pancreatic cancer initiating cells (PaCICs) can produce Cld7-positive exosomes which are capable of inducing re-programming of non-metastatic cancer cells to further increase their invasiveness [ 113 ].…”

“…Cld7 in tight junction (TJ-Cld7) is shown to regulate the entry of related proteins into PaCaExos and affect the function of exosomes derived from CICs (CIC-Exos) by modulating the composition of exosomal transporters and lipid metabolites, while Palm-Cld7-positive exosomes have the capability of regulating cell migration [ 113 ]. Importantly, Kyuno and colleagues have found that murine pancreatic cancer initiating cells (PaCICs) can produce Cld7-positive exosomes which are capable of inducing re-programming of non-metastatic cancer cells to further increase their invasiveness [ 113 ]. Another PaCa-derived Wnt5β-positive exosomes have been reported to enter and activate the Wnt5β signaling in other cancer cells lines such as PaCa, A549 and Caco-2, where they stimulate migration and proliferation.…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…Intracellular vesicle traffic remains to be defined (378). Alternatively, Exo-recruitment during biogenesis is not excluded (390) and would be consistent with pronounced coimmunoprecipitation of cldn7 with Golgi-endoplasmic reticulum (ER) transporters (391).…”