Because We Are All Different: The Hidden Geography of Drug Response

Cancer is often discussed as a single disease, but heterogeneity exists at every level, from differences between patients to differences among neighboring cells within the same tumor. With support from a 2024 Victoria’s Secret Global Fund for Women’s Cancers Career Development Award, in Partnership with Pelotonia and AACR, Medical Research Council Investigator Louise Fets, PhD, is advancing understanding of how heterogeneity within ovarian tumors influences drug response.

In a study published in Nature Communications, Dr. Fets and colleagues demonstrated that clinically important PARP inhibitors can distribute unevenly throughout high-grade serous ovarian tumors because individual cancer cells differ in their ability to accumulate the drugs (1). The findings point to an underexplored mechanism that may help explain variation in PARP inhibitor response among patients with ovarian cancer.

The Victoria’s Secret Global Fund for Women’s Cancers Career Development Awards, in Partnership with Pelotonia and AACR, support innovative research in breast and gynecologic cancers while investing in promising women scientists at the assistant professor level. Dr. Fets, a programme leader track group leader at the MRC Laboratory of Medical Sciences, hypothesized that heterogeneous drug distribution in high-grade serous ovarian cancer could contribute to patient-to-patient variability in PARP inhibitor response and represent an underrecognized mechanism of drug resistance. Her team found that differences in lysosomal content across tumor cells contributed to differential accumulation of the PARP inhibitors rucaparib and niraparib, and that these differences were associated with variation in cellular response to treatment.

To remove the influence of blood vessels on drug distribution, the researchers sectioned surgical tissue from patients with high-grade serous ovarian cancer and exposed the tissue slices to PARP inhibitors ex vivo. Mass spectrometry imaging revealed substantial heterogeneity in drug distribution across samples, with clear drug hotspots in some areas and little or no detectable drug in others. Single-cell experiments confirmed that this variability was not driven by genetically encoded differences within the bulk cancer cell population. The researchers also found that heterogeneous drug accumulation was linked to differences in DNA damage and PARP inhibitor efficacy at the single-cell level.

The researchers next found that increased PARP inhibitor accumulation was associated with lysosomal signatures. Live-cell imaging showed that rucaparib puncta colocalized with lysosomes within 30 minutes of treatment. Overexpressing transcription factor EB, a master regulator of lysosomal function and autophagy (2), increased intracellular rucaparib concentrations, while alkalinizing lysosomes with bafilomycin or chloroquine decreased them. Because PARP is localized in the nucleus, the team also measured nuclear accumulation of rucaparib and found that bafilomycin reduced nuclear drug levels across all tested concentrations. Additional washout experiments showed that rucaparib fluorescence declined more slowly in cells with intact lysosomal function than in cells treated with bafilomycin or chloroquine, further supporting a model in which lysosomes act as a reservoir that helps maintain higher cytosolic and nuclear rucaparib concentrations.

Looking ahead, Dr. Fets said her team aims to determine what drives heterogeneity in lysosomal content in ovarian cancer and whether that biology can be manipulated to improve drug distribution. They are also investigating how other therapeutics behave, because this form of drug-distribution heterogeneity may be widespread, underexplored, and relevant to treatment response for many patients.

Reflecting on the impact of the grant, Dr. Fets said, “AACR grant funding allowed me to continue to support the incredibly talented Dr. Carmen Ramirez Moncayo (first author on this work), capitalizing on the multi-modal imaging pipelines she had set up during her PhD in the lab. As well as this, being awarded this grant has enabled me to network internationally, meeting new inspiring colleagues and collaborators that I otherwise would not have had the opportunity to connect with.”

References

1. Moncayo CR, Restaudis R, Zhang G, Marks D, Ortega-Prieto P, et al. Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors. Nature Communications.  2026; 17:2546-63
2. Napolitano G, Ballabio A. TFEB at a glance. J Cell Sci. 2016; 129: 2475-81