Cell-level analysis reveals how ovarian tumors may develop resistance to chemotherapy

High-grade serous ovarian cancer is an aggressive form of ovarian cancer, characterized in particular by high diversity among the cells that compose a given tumor. This intratumor heterogeneity is a major challenge in understanding why some tumors respond to treatments and others resist. Additionally, this diversity is not limited to genetic differences: tumor cells that have similar genetic profiles may have different functions, depending on the genes they express and their epigenetic state.

To characterize this diversity, a research team from the CNRS, the Institut Curie and the Sorbonne Université used a sequencing approach at the scale of individual nuclei to analyze tumor cells individually and monitor how their molecular characteristics changed.

The study, appearing in the journal Cancer Discovery, was conducted in collaboration with startup One Biosciences, a spinoff from the Institut Curie co-founded by 2022 CNRS Innovation Medal laureate Céline Vallot, who is leading this study.

An innovative way to monitor how the tumor changes throughout treatment

First, 150 tumor biopsies from biobanks underwent this analysis. Then the method was used on 16 patients, before and after treatment, over a period of three to six months, as part of the longitudinal study SCANDARE.

The scientists observed patterns in how cells changed according to treatment response. In patients whose tumors responded to treatment, the scientists saw tumor cell division decrease or even stop completely, along with a reduction in cells that activate interferon-response pathways. These pathways involve molecules that play an important role in an organism’s immune response.

In contrast, in patients who did not respond to treatment, some tumor cell populations increased and activated pathways associated with resistance, in particular those related to TNFα, a molecule involved in the body’s inflammatory responses, and EMT, a process that changes cell properties, particularly adhesion and mobility.

The study also showed that a higher proportion of dividing cells at the time of diagnosis is associated with a better treatment response and longer overall survival.

Cells already ‘configured’ to resist before treatment

This raises the question: Do these cell states associated with resistance appear under the effect of treatment, or did they exist beforehand? Through epigenomic analyses, the scientists have shown that cells associated with chemoresistance are already “preconfigured” epigenetically to resist, even before the start of treatment.

However, this idea of epigenetic predisposition does not mean that the cells are already resistant, nor that they are necessarily destined to become resistant. It means that their initial state could facilitate the activation of programs associated with resistance when they are exposed to treatment.

These results show that DNA mutations alone do not explain treatment resistance, and they underline the importance of studying tumor cells before they are exposed to chemotherapy.

Promising prospects for improving patient care

These results must be confirmed in larger cohorts before this approach can be used clinically. They do, however, form a first step toward the development of diagnostic tools that will allow better mapping of tumor states to anticipate how they will change during treatment.

Beyond ovarian cancer, this approach is already used by One Biosciences in several cancer types, in collaboration with hospitals in Europe and the U.S. These efforts aim to better understand the mechanisms that determine response or resistance to treatments and may eventually help guide the choice of therapy more precisely for each patient.

The scientists have already identified candidate transcription factors and proteins involved in activating these resistance pathways. Understanding their roles more closely through further research could help identify new therapeutic targets and develop medicines that can block some mechanisms that encourage resistance.

This understanding could also help researchers explore new approaches aimed at limiting the capacity of tumor cells to change state during treatment.

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Andrew Zinin

Master’s in physics with research experience. Long-time science news enthusiast. Plays key role in Science X’s editorial success.

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