Browsing by Author "Prisco, Marco"

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    APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa
    (American Association for the Advancement of Science, 2018) Cho, Raymond; Alexandrov, Ludmil; den Breems, Nicoline; Atanasova, Velina; Farshchian, Mehdi; Purdom, Elizabeth; Nguyen, Tran; Coarfa, Cristian; Rajapakshe, Kimal; Prisco, Marco; Sahu, Joya; Tassone, Patrick; Greenawalt, Evan; Collisson, Eric; Wu, Wei; Yao, Hui; Su, Xiaoping; Guttmann-Gruber, Christina; Piñón, Josefina; Hashmi, Raabia; Fuentes, Ignacia
    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light–induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide–like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus–negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.
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    Cells from discarded dressings diferentiate chronic from acute wounds in patients with Epidermolysis Bullosa
    (2020) Fuentes, Ignacia; Guttmann‑Gruber, Christina; Tockner, Birgit; Diem, Anja; Klausegger, Alfred; Cofré‑Araneda, Glenda; Figuera, Olga; Hidalgo, Yessia; Morandé, Pilar; Palisson, Francis; Rebolledo-Jaramillo, Boris; Yubero, María Joao; Cho, Raymond J.; Rishel, Heather I.; Marinkovich, M. Peter; Teng, Joyce M. C.; Webster, Timothy G.; Prisco, Marco; Eraso, Luis H.; Hofbauer, Josefina Piñon; South, Andrew P.
    Impaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.
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    Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.
    (2019) Atanasova, Velina S.; Pourreyron, Celine; Farshchian, Mehdi; Christian A., Brown IV; Watt, Stephen A.; Wright, Sheila; Warkala, Michael; Guttmann-Gruber, Christina; Piñón Hofbauer, Josefina; Fuentes, Ignacia; Prisco, Marco; Rashidghamat, Elham; Has, Cristina; Palisson, Francis; Hovnanian, Alain; McGrath, John A.; Mellerio, Jemima E.; Bauer, Johann; South, Andrew P.
    Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC. Translational Relevance Collectively, our data support a clinical trial of rigosertib for treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma, an inherently aggressive subtype of squamous cell carcinoma with extremely low 5-year survival. Currently, there are no effective treatments for this devastating cancer, and often times, initial squamous cell carcinoma will recur and readily metastasize; any effective systemic therapy that reduces tumor burden will improve quality of life in this patient population.

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