👤 Leticia Oliveira-Ferrer

Epithelial protein lost in neoplasm (EPLIN), an actin-binding protein, has been described as both a tumor promoter and tumor suppressor in different cancers. The roles of EPLIN isoforms (α/β) remain largely unknown and could explain these opposing views. We observed distinct EPLIN isoform localization in breast cancer cells; EPLINα is recruited to actin in plasma membrane ruffles and endosomes, while EPLINβ resides on stress fibers. EPLINα localizes to early endosomes in an actin-dependent manner, where it interacts with Rab21, an established regulator of β1-integrin endosomal trafficking. This supports β1-integrin recycling and cell migration. Using proximity biotinylation (BioID), we identified coronin 1C as an EPLIN-proximal protein, which also localizes at Rab21-containing endosomes and controls integrin recycling downstream of EPLINα. EPLINα expression was linked to increased breast cancer cell motility, and a high EPLINα-to-EPLINβ ratio correlated with a mesenchymal phenotype in patient samples. Our work identifies previously unknown EPLIN-isoform-specific functions relevant to breast cancer and beyond. Show less

Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis and cancer invasion. Unlike cargo-specific clathrin-mediated endocytosis, the clathrin- and dynamin-independent endocytic pathway (CLIC-GEEC, CG pathway) is considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. While the core molecular players of CG-endocytosis have been recently defined, evidence of cargo-specific adaptors or selective uptake of proteins for the pathway are lacking. Here we identify the actin-binding protein Swiprosin-1 (Swip1, EFHD2) as a cargo-specific adaptor for CG-endocytosis. Swip1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery-Arf1, IRSp53 and actin-and is critical for integrin endocytosis. Through this function, Swip1 supports integrin-dependent cancer-cell migration and invasion, and is a negative prognostic marker in breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG pathway and a role for specific adaptors in recruitment into this endocytic route. Show less

Despite increasing incidence, vulvar squamous cell carcinoma (VSCC) is still a rare disease. Until now, two etiological pathways have been described: a high-risk human papillomavirus (HPV)-dependent route and an HPV-independent pathway often associated with lichen sclerosus. To date, therapeutic strategies in VSCC are not influenced by molecular pathological information and therapeutic options for advanced or recurrent disease are limited. Whole exome sequencing of DNA, isolated from 34 VSCC samples and matched normal tissue for each individual was performed on an Illumina HiSeq4000. Short variant discovery was carried out using BWA mem and FreeBayes. Variants were annotated using ANNOVAR. FIGO stages were: IB (n = 7), II (n = 11), III (n = 8), and IVA (n = 3), (n = 5 unknown). TP53 missense mutations were most commonly detected with 56% (19/34). 12/34 (35.3%) samples were HPV positive (all HPV16), HPV positivity and TP53 mutations were mutually exclusive (p < .0001). Additionally, we observed mutations in known cancer relevant genes, like NBPF1 (n = 7), MACF1 (n = 5), SYNE2 (n = 5), DOCK2 (n = 4), KMT2D (n = 4), MAP2 (n = 4), NACA (n = 4), PIK3CA (n = 4), SYNE1 (n = 4), FBWX7 (n = 3), MSH6 (n = 3), NSD1 (n = 3), POLE (n = 3), TSC2, (n = 3) and CDKN2A (n = 2), but at considerably lower frequencies. For the total cohort 1848 cancer related mutations were detected (median of 54.4 per sample). The key mutation in HPV negative vulvar carcinoma affects TP53. While a multitude of cancer related mutations was detected in various samples, only few mutations recur and/or affect concurrent signaling pathways. Show less