Róża Przanowska is a postdoctoral researcher at the University of Virginia. She maps the structural configurations of long non-coding RNAs (lncRNAs) to uncover how biomolecular heterogeneity drives therapeutic resistance in estrogen receptor-positive (ER+) breast cancer. In this Postdoc Portrait interview, she shares how unlocking the mysteries of lncRNAs could be the first step towards more personalized treatments for breast cancer.
Mapping lncRNA Structural Heterogeneity
Q | What drew you to the role of RNA in cancer?
I’ve always liked puzzles, and biology is full of them. My scientific journey started at the University of Warsaw in molecular biologist Andrzej Dziembowski’s lab where my project focused on the structural biology of the complex that regulates gene expression. During an internship in Thomas Braun’s group at Max Planck Institute, I studied the epigenetic regulation of differentiation processes. These experiences led me to a Fulbright scholarship in biochemist Anindya Dutta’s laboratory at the University of Virginia, where I continued as a PhD student with a focus on the non-coding RNAs in myogenesis with concurrent exposure to cancer biology, DNA damage, and replication. By the end of my PhD, I knew I would like to focus on cancer biology to identify how functional lncRNA structures affect cancer development, progression, and therapy resistance. Thus, I joined bioengineer Kevin Janes’s laboratory at the University of Virginia, where I currently work as a postdoctoral research associate on lncRNA heterogeneity in ER+ breast cancer.
Q | What scientific problem are you trying to solve?
The overarching goal of my research program is to identify lncRNAs that meaningfully distinguish ER+ breast cancers based on differences in expression, structure, and function.
Approximately 70 percent of all breast cancers are ER+, and although many initially respond to therapy, 40–50 percent develop or acquire treatment resistance. Differences in disease progression are thought to arise from variations between tumors and among cells within a tumor. There is a need for a deeper understanding of the biological variability in ER+ breast cancers to identify novel diagnostic tools and, eventually, therapeutics that specifically target the driving heterogeneities.
One underappreciated class of biomolecular heterogeneity involves lncRNAs, which are versatile regulators of cancer-relevant processes and highly variable in their expression, structure, and function. LncRNAs encode untranslated RNA transcripts greater than 200 nucleotides that impact numerous molecular processes, including cell-cycle regulation, transcription-factor binding, and protein-RNA localization. LncRNA pleiotropy stems from interactions with other biomolecules through complex base pairing into structural folds. Structural domains, once identified and functionally validated, are readily disrupted by antisense oligonucleotides or small molecules.
My research will define molecular mechanisms by which lncRNAs promote ER+ breast cancer and establish a framework for structure-driven lncRNA targeting to address cancer heterogeneity.
Overcoming Resistance in Breast Cancer
Q | What’s one thing you learned from experimental probing versus prediction algorithms that you didn’t expect?
My research was full of surprises. I like to say that biology is messy, and by studying it, we get closer to understanding what every ball of yarn means functionally. One of the particularly unexpected results was in the study of the structure-function relationship of MyoD upstream noncoding (MUNC) lncRNA. I built experimentally driven models of secondary structures of MUNC lncRNAs using selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP). Experimental probing of the RNA structure revealed that MUNC contains multiple structural domains not detected by prediction algorithms lacking experimental information. We showed that these specific and structurally distinct domains are required for the induction of promyogenic genes, for binding genomic sites and gene expression regulation, and for binding the cohesin complex. Surprisingly, MYOD1 induction and cohesin interaction comprise only a subset of the MUNC phenotype. This study revealed unexpectedly complex, structure-driven functions for the MUNC lncRNA and emphasized the importance of experimentally determined structures for understanding structure-function relationships in lncRNAs.
Q | If your research succeeds, what could it change for science or society?
While many patients with ER+ breast cancer initially respond well to treatment, a large number eventually face relapse, sometimes many years later. About one in 10 women will develop cancer that spreads within 10 years, which is far more difficult to treat. My research aims to understand why that happens and to find new ways to prevent it, with the ultimate goal of improving long-term survival and quality of life for patients. LncRNAs have been called a “final frontier” for gene discovery, but we still don’t know the patterns in the way they fold and interact. Once we understand how lncRNAs function in ER+ breast cancer, we may be able to design a new class of personalized treatments. One especially promising approach is to use small, custom-made drugs called antisense oligonucleotides (ASOs), which can specifically block harmful lncRNAs. Because ASO therapies are already proving successful in other diseases, adapting them to breast cancer is ambitious but realistic. If successful, this work could provide new therapeutic strategies for ER+ breast cancer while establishing tools and principles broadly applicable to other cancers and diseases.
Q | What question are you most excited to answer next?
While many lncRNAs have been implicated in cancer, their functions in cancer often arise from repurposing normal developmental programs. Once my lab is established, we will investigate how lncRNA structure governs biological activities during lineage specification and differentiation. By comparing structural dependencies in development versus cancer contexts, we will clarify how RNA structure evolves to support complex cellular transitions.
Responses have been edited for length and clarity.
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