Nucleases, cancer and immunity

Nucleases play a crucial role in the maintenance of the genome stability as well as in the regulation of the innate immune response to self and non-self nucleic acids. Indeed, alterations in some nucleases have been associated with carcinogenesis and inflammatory diseases. In this regard, functional studies are revealing specific and non-redundant biological roles for many of these genes.

• Deciphering the function and dysfunction of TREX2
  Research in our laboratory is focused on the exonuclease TREX2. In this regard, our studies have been pioneering in unraveling the specific expression of TREX2 in keratinocytes and its key role in skin carcinogenesis and psoriasis. TREX2 contributes to DNA degradation in keratinocytes suffering DNA damage or accelerated turnover, promoting thus keratinocyte death and subsequent skin inflammation.
  Ongoing studies in the laboratory pursue to understand and gain insights in the relevance and mechanisms of TREX2 in skin homeostasis and pathogenesis.

• TREX2 targeting in Psoriasis

  The fact that Trex2 deficiency leads to a decreased psoriatic inflammation has unmasked

  TREX2 as a novel target for breakthrough keratinocyte-based psoriasis treatments, which can further overcome immunosuppressive side effects associated to available therapies targeting key immune system players. Indeed, we have identified and developed the first-in-class TREX2 inhibitors, which have shown promising results as therapeutics for psoriasis. We envisage developing an effective, specific, and safe small molecule drug with a high therapeutic index to treat psoriasis, and other TREX2-driven diseases, and to promote its translation into clinical applications.

• Knödlseder N, Fábrega MJ, Santos-Moreno J, Manils J, Toloza L, Marín Vilar M, Fernández C, Broadbent K, Maruotti J, Lemenager H, Carolis C, Zouboulis CC, Soler C, Lood R, Brüggemann H, Güell M.   

Delivery of a sebum modulator by an engineered skin microbe in mice | Nature Biotechnology

Nat Biotechnol. 2024 

• Llorente X, Esteruelas G, Bonilla L, Agudelo MG, Filgaira I, Lopez-Ramajo D, Gong RC, Soler C, Espina M, García ML, Manils J, Pujol M, Sánchez-López

Riluzole-Loaded Nanostructured Lipid Carriers for Hyperproliferative Skin Diseases (mdpi.com) 

Int J Mol Sci. 2023;24(9):8053.

• Manils J, Marruecos L, Soler C.

Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer.
Cells. 2022 Jul 9;11(14):2157.
 

• Marruecos L, Manils J, Moreta C, Gómez D, Filgaira I, Serafin A, Cañas X, Espinosa L, Soler C

Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression.

Cell Death Dis. 2021 Apr 6;12(4):359.

• Matera C, Gomila AMJ, Camarero N, Libergoli M, Soler C, Gorostiza P.

Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy.

J Am Chem Soc. 2018, 140(46):15764-15773.

• Manils J, Fischer H, Climent J, Casas E,  García-Martínez C, Bas J, Vavouri T, Ciruela F, de Anta JM, Tschachler E, Eckhart L, and Soler C.

Double deficiency of Trex2 and Dnase1L2 nucleases leads to accumulation of DNA in lingual cornifying keratinocytes without activating inflammatory responses.
Sci Rep, 2017, 7(1):11902.

• Manils J, Casas E, Viña-Vilaseca A, Lopez M, Díez-Villanueva A, Gómez D, Marruecos L, Ferran M, Benito C, Perrino FW, Vavouri T, de Anta JM, Ciruela F, and Soler C.

The exonuclease TREX2 shapes psoriatic phenotype.
J Invest Dermatol, 2016, 136(12):2345-55.

• Manils J, Gómez D, Salla-Martret M, Fischer H, Fye JM, Marzo E, Marruecos L, Serrano I, Salgado R, Rodrigo JP, Garcia-Pedrero JM, Serafin AM, Cañas X, Benito C, Toll A, Forcales SV, Perrino FW, Eckhart L, Soler C.

Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.
Oncotarget, 2015, 6(26):22375-96.

• Parra D, Manils J, Castellana B, Viña-Vilaseca A, Morán-Salvador E, Vázquez-Villoldo N, Tarancón G, Borràs M, Sancho S, Benito C, Ortega S, Soler C.

Increased Susceptibility to Skin Carcinogenesis in TREX2 Knockout Mice.
Cancer Res. 2009, 69(16):6676-84.

• Research ID (L-1185-2014)

• ORCID (0000-0001-6502-5012)