CRISPR-based drug target discovery in cancer and autoimmunity

Using experimental systems and patient material, we study the immune system with specific interests related to autoimmune disease and cancer therapy.

Fredrik Wermeling
Fredrik Wermeling, Photo: Karin Nordin.

A major part of the different projects in the lab involves using CRISPR-based custom screens as a discovery platform to understand complex biological processes and to identify novel drug targets. To facilitate the design of these custom screens, we have developed a freely accessible web-based software called Green Listed that can be accessed here. A review describing bioinformatics tools we use designing and analyzing hypothesis-driven CRISPR screens can be found here (Iyer VS et al., 2020). Related CRISPR plasmids that we have deposited at the non-profit repository Addgene are found here.

Examples of how we work with CRISPR for discovery in vitro and in vivo is found here (Shen Y et al., 2021, where we describe the Rapid CRISPR Competitive/RCC assay and the ImmunoCRISPR/iCR model system), as well as here (Jiang L et al., 2021, Cancer Research, where we study the CRISPR DNA damage response).

Several projects in the lab also relate to our interest in signaling downstream of the IL-4 receptor (IL-4R). The basis for this interest was the unexpected finding that the expression of the IL-4R is essential for the activity of a drug (IVIG) used to treat patients with autoimmune disease and that the expression of this receptor is highly regulated during inflammation (Anthony RM et al., 2011, Nature, and Wermeling F et al., 2013, PNAS). Recently we published a study describing how IL-4 can affect neutrophils, and consequences of this in the autoimmune setting (Panda SK et al., 2020, PNAS).

Group members

Fredrik Wermeling, PhD, Associate Professor , PI

Vaish S Iyer, PhD student

Yunbing Shen, PhD student

Zhaojun Li, PhD student

Sanjay Boddul, Postdoc

Zsolt Kasza, PhD, Lab manager

Funding

  • The Swedish Research Council
  • Swedish Cancer Society
  • Karolinska Institutet (Faculty Funded Career Positions)
  • Swedish Foundation for Strategic Research (Ingvar Carlsson Award 2013)
  • Wenner-Gren Foundations (Wenner-Gren Fellow program)
  • King Gustaf V 80-Year Foundation
  • Jeansson Foundations
  • The Alfhild Aquilin and Karl Bensen Memorial Foundation, and the Gösta and Karin Wahmans Memorial Foundation
  • Alex and Eva Wallström Foundation for scientific research and education
  • Åke Wiberg Foundation
  • Börje Dahlin Foundation

Selected publications

CRISPR/Cas9-Induced DNA Damage Enriches for Mutations in a p53-Linked Interactome: Implications for CRISPR-Based Therapies.
Jiang L, Ingelshed K, Shen Y, Boddul SV, Iyer VS, Kasza Z, Sedimbi S, Lane DP, Wermeling F
Cancer Res 2022 01;82(1):36-45

A rapid CRISPR competitive assay for in vitro and in vivo discovery of potential drug targets affecting the hematopoietic system.
Shen Y, Jiang L, Iyer VS, Raposo B, Dubnovitsky A, Boddul SV, Kasza Z, Wermeling F
Comput Struct Biotechnol J 2021 ;19():5360-5370

Designing custom CRISPR libraries for hypothesis-driven drug target discovery.
Iyer VS, Jiang L, Shen Y, Boddul SV, Panda SK, Kasza Z, Schmierer B, Wermeling F
Comput Struct Biotechnol J 2020 ;18():2237-2246

IL-4 controls activated neutrophil FcγR2b expression and migration into inflamed joints.
Panda SK, Wigerblad G, Jiang L, Jiménez-Andrade Y, Iyer VS, Shen Y, Boddul SV, Guerreiro-Cacais AO, Raposo B, Kasza Z, Wermeling F
Proc Natl Acad Sci U S A 2020 02;117(6):3103-3113

Green listed-a CRISPR screen tool.
Panda SK, Boddul SV, Jiménez-Andrade GY, Jiang L, Kasza Z, Fernandez-Ricaud L, Wermeling F
Bioinformatics 2017 04;33(7):1099-1100

Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling.
Wermeling F, Anthony RM, Brombacher F, Ravetch JV
Proc. Natl. Acad. Sci. U.S.A. 2013 Aug;110(33):13487-91

Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway.
Anthony RM, Kobayashi T, Wermeling F, Ravetch JV
Nature 2011 Jun;475(7354):110-3

Invariant NKT cells limit activation of autoreactive CD1d-positive B cells.
Wermeling F, Lind SM, Jordö ED, Cardell SL, Karlsson MC
J. Exp. Med. 2010 May;207(5):943-52