New Method Traces Pre-existing Resistance in Cancer Cells, Opening Doors for Targeted Therapies

New Method Traces Pre-existing Resistance in Cancer Cells, Opening Doors for Targeted Therapies

(IN BRIEF) A recent study published in Nature Communications by researchers at the University of Helsinki introduces a groundbreaking methodology called ReSisTrace, designed to identify and trace pre-existing treatment resistance in cancer cells. By labeling cancer cells with genetic barcodes and analyzing single-cell gene expression, the researchers uncovered genes associated with proteostasis and mRNA surveillance that contribute to treatment resistance in high-grade serous ovarian cancer. Leveraging this knowledge, Associate Professor Jing Tang’s laboratory predicted small molecules capable of shifting resistant cells to sensitive states, thereby enhancing sensitivity to chemotherapy, PARP inhibitors, and innate immunity. This innovative approach offers insights into the development of sequential cancer therapies to preempt resistance emergence, potentially revolutionizing cancer treatment strategies.

(PRESS RELEASE) HELSINKI, 12-Feb-2024 — /EuropaWire/ — In many cancers, such as ovarian cancer, each round of chemotherapy kills the majority of cancer cells, while a small population of them survives through treatment. These cells are typically more resistant for the next cycle of therapy and can thus regrow to a deadly, treatment resistant tumour.

In a recent study published in Nature Communications, researchers at the University of Helsinki wanted to know how this small population of surviving cells differs from the other more sensitive cells already before the treatment. To enable this cellular time travel, they developed ReSisTrace, a methodology that takes advantage of the similarity of sister cells to trace back pre-existing treatment resistance in cancer.

Labeling cancer cells with genetic barcodes

“In ReSisTrace, we label cancer cells uniquely with genetic barcodes and allow them to divide once, so that we get two identical sister cells that share the same barcode. We then analyse single-cell gene expression from half of the cells before the treatment, while treating the other half with chemotherapy, or other anti-cancer treatment. From the surviving cells we can identify the barcodes of resistant cells. Using their sister cells analysed before the treatment, we can discover how the cells that will survive through treatment differ from the pre-sensitive cells, thus revealing the pre-existing resistant states”, says Jun Dai, PhD student in Anna Vähärautio’s group, who developed the methodology to trace sister cells.

The method was applied to reveal resistant cell states against chemotherapy, targeted therapy or innate immunity in high-grade serous ovarian cancer. “We found that genes associated with proteostasis and mRNA surveillance are important to explain pre-existing treatment resistance.  Interestingly, we found that DNA repair deficiency that is very common in ovarian cancer, sensitised these cells to not only chemotherapy and PARP inhibitors but also to NK killing”, says Shuyu Zheng, a PhD student from Jing Tang’s group, who spearheaded the computational analysis.

Associate Professor Jing Tang’s laboratory then leveraged the revealed gene expression changes to predict small molecules that could shift the cells from a resistant state to a sensitive state.

“We developed a computational method to correlate the resistant states with the gene expression changes induced by a drug. Ideally, if a drug can reverse the resistant cells’ gene expression profiles, then it can be considered as a potential hit to overcome the resistance”, says Associate Professor Jing Tang, and a team leader in Systems Oncology Research program, University of Helsinki.

Researchers found that most of the predicted small molecules indeed changed the gene expression patterns of cancer cells towards sensitive states. Most importantly, after adding these drugs, cancer cells were significantly more sensitive to carboplatin, PARP inhibitor or NK killing, illustrating that the pre-resistance states identified by ReSisTrace were functionally relevant and targetable.

“Our novel experimental-computational approach really leverages the power of single-cell omics and pharmacological data integration”, Associate Professor Jing Tang summarises.

Widely applicable method to identify and target pre-existing resistant cell states across cancer types

“The method we developed reveals the features of cells that will – in the future – become resistant to anti-cancer treatments by coupling cell state and fate in sister cell resolution. It is widely applicable to identify and target pre-existing resistant cell states across cancer types, as well as against different treatment modalities, including immunotherapies. Our approach paves the way for development of sequential cancer therapies that can block resistance before it even emerges”, concludes Anna Vähärautio, K. Albin Johansson Cancer Research Fellow, Foundation for the Finnish Cancer Institute and a team leader in Systems Oncology Research program, University of Helsinki.

Media Contacts:

Anna Vähärautio
University Researcher
RESEARCH PROGRAM SYSTEMS ONCOLOGY
anna.vaharautio@helsinki.fi
0294125550

Jing Tang
Associate Professor
DEPARTMENT OF BIOCHEMISTRY AND DEVELOPMENTAL BIOLOGY
jing.tang@helsinki.fi

SOURCE: University of Helsinki