Heterogeneous Tumors: Why one drug is often not enough
Heterogeneity within the tumors requires more than one drug.
Tumors can behave differently in patients. This has already been well investigated and is a part of personalized-therapy concepts. The differences of a tumor within a patient are, however, less well known. These differences are called intratumoral heterogeneity. Heterogeneity can also influence the effectiveness of the therapy. In this project, e:Med scientists have inspected intratumoral differences and investigated transcription (scRNA-Seq), genetics and drug response in the different cells of B-cell lymphoma. The Heidelberg team could identify up to four different subpopulations within the same tumor, each of which reacted differently to specific drugs. These results show that intratumoral heterogeneity may be an important component of personalized therapy in the future.
Not all tumor are the same
In cancer therapy, often a single drug does not achieve an effective response. Usually, only a combination of several drugs can keep the tumor in check. This points to different abnormalities in the tumor cells.
In addition, there are different cancer cells within a tumor, but also non-malignant cells in the immediate vicinity. Especially in B-cell lymphomas, it is known that interaction between lymphoma and immune cells can be crucial for the response of therapy. With technologies such as single-cell sequencing, it is possible to describe the different cells and areas of a tumor and the non-malignant immune cells in their environment.
The researchers around Sascha Dietrich and Tobias Roider of the e:Med junior research group SYMPATHY examined the cells of the tumor and furthermore also the T-cells in the immediate vicinity of the tumor. The researchers found that the different T-cell subgroups were very similar in all patients. However, there was a significant variation in the size of the individual subgroups. Thus, the tumors appear to have an influence on the recruitment of specific T cell subgroups, but not on the expression profiles of the T cells.
Drug tests show a difference within a tumor
In the next steps, the scientists sorted the tumor cells out by flow cytometry, analyzed genetically, and tested for different drugs. The researchers could detect up to four subpopulations with different drug responses in a single tumor. By analyzing the cells at different levels, they were able to determine which genetic aberration was responsible for altered expression and ultimately for the response to certain drugs. Derived from these ex-vivo experiments, a clinical trial was conducted to predict which drugs would be effective in a patient.
This study shows how a systems medical analysis of tumors can help to find the optimal therapy and thus enable stratified cancer therapy.
Original Publication:
Roider, T., J. Seufert, A. Uvarovskii, F. Frauhammer, M. Bordas, N. Abedpour, M. Stolarczyk, J.-P. Mallm, S. A. Herbst, P.-M. Bruch, H. Balke-Want, M. Hundemer, K. Rippe, B. Goeppert, M. Seiffert, B. Brors, G. Mechtersheimer, T. Zenz, M. Peifer, B. Chapuy, M. Schlesner, C. Müller-Tidow, S. Fröhling, W. Huber, S. Anders and S. Dietrich (2020). "Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels." Nat Cell Biol: 1–11. https://doi.org/10.1038/s41556-020-0532-x.
Scientific Contact:
PD Dr. Sascha Dietrich, e:Med Nachwuchsgruppe SYMPATHY
University Clinic Heidelberg