Carina Strell – How cellular ecosystems drive early breast cancer progression and therapy response

Breast cancer develops from atypical hyperplasia, through ductal carcinoma in situ (DCIS) to invasive carcinoma. However, only few DCIS lesions progress to invasive breast cancer. Since underlying evolutionary processes are largely unknown, the biological and clinical prediction of progression remains difficult. This leads to over- and undertreatment of women with early breast cancer that routinely receive adjuvant radiotherapy.

Mechanisms behind disease progression

Our projects focus on the hypothesis that already within early breast cancer lesions, cellular ecosystems exist, where localised tumour-stroma interactions synergistically drive disease progression and response to radiotherapy. We aim to reconstruct these regulatory mechanisms of early breast cancer through spatial analyses of diagnostic tissue samples by state-of-the art in situ techniques.

In order to spatially connect genotypic (subclonal expansion) and phenotypic cellular properties (cellular phenotypes and activation states), we combine in situ sequencing and in situ hybridisation approaches with multiplex immunofluorescence as well as imaging mass cytometry. We also developed proximity ligation assays to outline targetable signalling pathway activation and immune checkpoint interactions directly in the tissue context.

Characterisation of breast cancer patient samples

The foundation of our projects is our breast cancer cohort, which includes tissue samples from patients with benign lesions (PASH, sclerosing adenosis), precursor lesions (atypical hyperplasia), DCIS, DCIS recurrences (with information on radiotherapy) well as invasive breast cancer samples from different stages including metastasis. An in-depth characterisation of our cohort with RNA and DNA sequencing is currently ongoing.

With our work we hope to develop a refined risk and treatment stratification for early breast cancer patients and ultimately also to identify new therapeutical targets and strategies for breast cancer patients resistant to current treatment modalities.