Exploiting metabolic dependencies, tumor plasticity and their consequences for drug response of HCL
Marc Seifert
PhDInstitute of Cell Biology (Tumor Research) at the Medical school Essen
Project Term: October 1, 2021 - September 30, 2024
We have long standing experience in the field of HCL research. The aim of this research proposal is to characterize HCL on single cell level across multiple layers to uncover interactions of HCL with its microenvironment, which supports HCL cell survival. We will further explore metabolic and functional dependencies of primary HCL cells, and we hypothesize that their attenuation compromises HCL cell survival. Finally, we aim to pharmacologically disrupt these pro-survival pathways in HCL cells.
Hairy cell leukemia is a disease caused by transformed B lymphocytes that repress normal Blood formation. HCL cells have unique features, which were enquired by hijacking and perturbing normal B cell functions. A better understanding of these functions is crucial to develop strategies to eradicate HCL cells. The mainstay of HCL treatment has been chemotherapy, targeting the growth of HCL tumors. Moreover, we and others successfully explored the inhibition of an important survival factor (BRAF) to treat HCL. Still, both treatment strategies are not curative, chemotherapy can have severe side-effects, and BRAF inhibitors induce rapid remissions, but they leave HCL cells behind that restore the tumor mass short after treatment is stopped. Thus, we need to improve our knowledge how HCL cells survive and persist, even under successful treatment. The aim of this study is to search for additional, specific HCL features that can be targeted to disrupt their life cycle. Our strategy is a comprehensive investigation of HCL cell biology and its surrounding tissue. To achieve this, we compare HCL cells to their normal B cell counterpart, and then identify the specific perturbations and survival strategies that caused malignant outgrowth. We showed that HCL cells are highly similar to B cells of the marginal zone (sMZ), a specialized tissue in the spleen. When activated, sMZ-B cells acquire a migratory phenotype, develop cell protrusions (“hairy cells”) and migrate until they reach a specialized environment (“survival niche“) where they settle down and survive. We assume that the BRAF-factor inhibits this terminal development and keeps the “hairy cells” frozen in a state of activity, migration, and search for survival signals, and our combined research supports this idea. Notably, this scenario indicates many pathways that contribute to HCL survival, including metabolic dependencies (active, migratory B cells consume a lot of energy), homing to specialized survival niches (HCL cells rely on interaction with normal tissue), and finally, avoidance of apoptosis: a normal B cell that gets activated but does not terminally differentiate would kill itself. We have indication that HCL cells avoid mortality via a distinct expression of pro-survival factors. The aim of this proposal is to investigate the above-described features of HCL cells, to estimate whether they may serve as specific vulnerabilities and exploit the possibility to use them to kill HCL cells.
The Hairy Cell Leukemia Foundation (HCLF) and The Leukemia & Lymphoma Society (LLS) have joined forces to create the HCL2025 program to support targeted research to build a more comprehensive foundational understanding of the molecular basis of hairy cell leukemia (HCL), develop additional therapies, and optimize outcomes for patients with this disease.