Research team Per Hydbring

Coding and non-coding RNAs in cancer

MicroRNA expression across 5000 human tumor samples. Adapted  from Hydbring et al., Cancer Cell, 2017.
MicroRNA expression across 5000 human tumor samples. Adapted from Hydbring et al., Cancer Cell, 2017.

Research

Our research is focused around uncovering coding and non-coding RNAs, involved in resistance to targeted therapies in cancer. In particular, we are focusing on microRNAs modulating refractoriness to Tyrosine Kinase Inhibitor (TKI) treatment in lung cancer, and how to deliver microRNA-based drugs into lung tumor models.

​MicroRNAs suppress target genes by nucleotide pairing to the 3’UTR of messenger RNAs, thereby tuning gene expression with each microRNA able to regulate numerous genes. 

During recent years, microRNA therapies have come under the development for a wide variety of diseases, including cancer. Delivery of microRNAs can be carried out using synthesized mimic-, or inhibitory molecules. The mimic molecule approach is based on introducing a synthetic molecule that is identical to a microRNA lost in cancer, while the inhibitory approach relies on specifically blocking microRNAs aberrantly expressed in cancer. 

Due to the promiscuous nature of microRNAs, delivery of microRNA drugs provides an ability to target multiple factors in single or overlapping signaling pathways. Hence, modulation of microRNAs may be particularly interesting when targeting refractory cancers.

We have established multiple methods in the laboratory to systematically uncover RNAs, including microRNAs, of specific importance for therapy refractoriness. Moreover, we have experience in formulating RNA-molecules into lipid nanoparticle vehicles for systemic in vivo delivery.​

Projects​

  1. RNAs in treatment-refractory lung adenocarcinomas

The majority of all lung cancers are classified as lung adenocarcinomas. A fraction of these cancers harbor mutations in receptor tyrosine kinases (RTKs), including EGFR and ALK, making them amenable for targeted therapy through tyrosine kinase inhibitors (TKIs). TKIs targeting these RTKs display superior efficacy in the clinic compared to chemotherapy and have quickly been established as standard of care for lung cancer patients with activating mutations in specific RTKs.  Although most patients respond in a favorable way to TKI-treatment, therapy resistance eventually emerges. Our aim in this project is to uncover diagnostic profiles as well as therapeutic molecular candidates among coding and non-coding RNAs of specific importance for TKI resistance in lung adenocarcinomas.​

  1. The role of microRNAs in cell-cycle driven cancers 

One of the main physiological alterations in cancer is self-sufficiency in growth signals. Growth signaling induces expression of cyclins, which subsequently recruit and activate their kinase partners, cyclin-dependent kinases (CDKs). Together, they form complexes that govern DNA-synthesis and cell division. Analysis across human tumors has revealed that cyclins and CDKs belong to the most frequently amplified genes across human cancer, including in lung cancers. Conversely, endogenous cell cycle inhibitory genes belong to the most frequently lost in cancers. We recently demonstrated that specific microRNAs, enriched in targeting multiple cell-cycle components, were highly efficacious in targeting refractory cancer types in vitro and in vivo, including triple negative breast cancers and KRAS-driven lung cancers. Our aim in this project is to expand on our previous findings to uncover microRNAs of particular importance for the cell cycle machinery in lung adenocarcinomas. ​

Team members

Per Hydbring, PhD, Research Team Leader
Zeinab Kosibaty, PhD, Post-doctoral fellow
Dominika Kazmierczak, PhD student
Simon Ekman, MD, PhD, Group Leader

Selected publications

An immune gene expression signature distinguishes central nervous system metastases from primary tumours in non-small-cell lung cancer.
Tsakonas G, Lewensohn R, Botling J, Ortiz-Villalon C, Micke P, Friesland S, Nord H, Lindskog M, Sandelin M, Hydbring P, Ekman S
Eur J Cancer 2020 06;132():24-34

miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC.
Lai Y, Kacal M, Kanony M, Stukan I, Jatta K, Kis L, Norberg E, Vakifahmetoglu-Norberg H, Lewensohn R, Hydbring P, Ekman S
Biochem Biophys Res Commun 2019 04;511(2):260-265

Exosomal RNA-profiling of pleural effusions identifies adenocarcinoma patients through elevated miR-200 and LCN2 expression.
Hydbring P, De Petris L, Zhang Y, Brandén E, Koyi H, Novak M, Kanter L, Hååg P, Hurley J, Tadigotla V, Zhu B, Skog J, Viktorsson K, Ekman S, Lewensohn R
Lung Cancer 2018 10;124():45-52

Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers.
Hydbring P, Wang Y, Fassl A, Li X, Matia V, Otto T, Choi YJ, Sweeney KE, Suski JM, Yin H, Bogorad RL, Goel S, Yuzugullu H, Kauffman KJ, Yang J, Jin C, Li Y, Floris D, Swanson R, Ng K, Sicinska E, Anders L, Zhao JJ, Polyak K, Anderson DG, Li C, Sicinski P
Cancer Cell 2017 04;31(4):576-590.e8

Identification of cell cycle-targeting microRNAs through genome-wide screens.
Hydbring P, Wang Y, Bogorad RL, Yin H, Anderson DG, Li C, Sicinski P
Cell Cycle 2017 ;16(23):2241-2248

Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases.
Hydbring P, Malumbres M, Sicinski P
Nat Rev Mol Cell Biol 2016 05;17(5):280-92

Clinical applications of microRNAs.
Hydbring P, Badalian-Very G
F1000Res 2013 ;2():136

The requirement for cyclin D function in tumor maintenance.
Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H, Sicinski P
Cancer Cell 2012 Oct;22(4):438-51

A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells.
Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, Zhai H, Vidal M, Gygi SP, Braun P, Sicinski P
Cancer Cell 2011 Nov;20(5):620-34

Funding bodies:

Vetenskapsrådet, Radiumhemmets Forskningsfonder