Interview with PD Dr. Laura Hinze

Department of Pediatric Hematology and Oncology, MHH

Copyright: Christian Wyrwa

What is your research focus and what are your main research questions?
The main focus of our research is to better understand molecular determinants of treatment resistance in malignant cells. In this context, survival under stress conditions such as an amino acid deficiency is of paramount importance for cancer cells. Some cells are vulnerable to an asparagine depletion, which is exploited therapeutically by the use of the bacterial enzyme asparaginase. Asparaginase dose-intensification has been a major driver of improved clinical outcomes in T-cell and B-cell acute lymphoblastic leukemias (T-ALL and B-ALL). However, resistance to asparaginase-based treatment regimens is a common clinical problem with a poor prognosis.

The core of our research is to dissect how amino acid metabolism is interconnected with growth control in drug resistant cancer cells, and how its molecular regulation can be used for therapeutic targeting.

What are findings you are excited about?
We recently found that drug-resistant leukemias as well as colorectal cancer (CRC) cells rely on proteasomal degradation as an alternative source of amino acids to survive an asparagine depletion. Asparaginase sensitization is mediated by a β-catenin independent branch of Wnt signaling, termed Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein degradation. Thus, Wnt/STOP inhibits generation of amino acids by catabolic protein degradation, and limits cellular asparagine availability creating a unique vulnerability in cancer cells that are as diverse as leukemias and CRC. Our studies implicate a central role for regulated protein degradation in cancer cells, and shed fundamental insights into a previously unrecognized mechanism of amino acid homeostasis in cancer cells.

Additionally, we have been able to identify that resistance to asparagine starvation is uniquely dependent on the highly-conserved N-terminal low-complexity domain of GSK3α, which is lacking in its paralog GSK3β. In response to depletion of specific amino acid this domain mediates the supramolecular assembly of GSK3α with ubiquitin-proteasome system components in membraneless cytoplasmic bodies. Thus, biomolecular condensation of GSK3α represents a previously unrecognized cellular mechanism to promote catalytic efficiency of protein degradation in response to amino acid starvation, an adaptive response co-opted by cancer cells for asparaginase resistance.

What kind of techniques and methods do you use for your research?
We use a variety of techniques and methods to integrate both basic molecular tools and patient-derived samples to model the complex interaction of amino acid metabolism and drug resistance. Thus, our ongoing projects encompass genetic engineering of cell-culture based models, co-immunoprecipitations, immunofluorescence analyses, confocal microscopy, transcriptomics and proteomics analyses. In addition, we developed genetically-engineered mouse models to study regulated protein degradation machineries in malignant as well as benign cells.

Why did you choose your research focus?
I was always interested in understanding how nutrient availability is driving tumor cell growth and cancer cell heterogeneity. In this context, it is particularly exciting for me to decipher the delicate balance of protein metabolism and catabolism through the proteasome, and how malignant cells sense amino acid insufficiency to trigger regulatory mechanisms of cellular homeostasis.

How did you become a researcher? Which institutions shaped your work and career?
Discovering something novel, and contributing to improve cancer therapy have been the main drivers of my research excitement. During my MD thesis at Hannover Medical School, I had an outstanding supervisor, who has been really supportive and further strengthened my research interest. After finishing the work of my thesis, I went on to do a postdoctoral internship at Boston Children’s Hospital/Dana Farber Cancer Institute. Training at such an outstanding institute with a great mentor and an amazing scientific community of senior and early career scientists further shaped my work. Subsequently, I moved back to Hannover for my first group leader position in the department of pediatric hematology and oncology.

How can your translational research activities benefit from the CCC-N research structure?
The collaboration of Hannover and Göttingen provides a unique and powerful platform to share and further develop translational/clinical models, basic molecular tools and a variety of innovative technologies including pre-clinical mouse models. The CCC-N thus allows to build joint forces and to increase the scientific exchange between participating researchers.

Can you tell us a little about your working group?
Our group has been located at MHH for more than 3 years now. Currently, we are 9 members in total. The core staff consists of a highly experienced senior scientist (biochemist) and a technician. We have one dedicated bioinformatician with an additional educational background in cell physiology. Furthermore, we have three excellent PhD students (biomedicine background) who are working on their theses. Two talented MD students are completing our group.

How can patients benefit from your research?
Large parts of our research relate to basic science, and it is hard to precisely predict when patients can benefit from the generated findings. However, our recent results provide a compelling rationale for the therapeutic potential of GSK3a inhibition and asparaginase, and currently build the basis for a clinical trial in a specific subgroup of metastatic colorectal cancer patients. Additionally, our finding of GSK3a-mediated supramolecular assembly provides the basis for the establishment of a new biomarker for asparaginase response in acute leukemias, which would for the first time allow to prospectively discriminate patients that respond to chemotherapeutic reagents such as asparaginase from those that do not.

What is the biggest challenge in cancer research?
One of the major challenges in cancer research is the complex heterogeneity in cancer cells, which drives response and resistance towards conventional chemotherapy. Thus, it is crucial i) to establish individualized biomarkers that allow to discriminate cells that do respond to treatment from those that do not respond, and ii) to identify novel therapeutic targets that are specifically toxic to resistant cancer cells, but not to normal cells.

Selection of publications

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias. Hinze L, Pfirrmann M, Karim S, Degar J, McGuckin C, Vinjamur D, Sacher J, Stevenson KE, Neuberg DS, Orellana E, Stanulla M, Gregory RI, Bauer DE, Wagner FF, Stegmaier K, Gutierrez A. Cancer Cell. 2019 Apr 15;35(4):664-676.e7. doi: 10.1016/j.ccell.2019.03.004. PMID: 30991026; PMCID: PMC6541931.

Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy. Hinze L, Labrosse R, Degar J, Han T, Schatoff EM, Schreek S, Karim S, McGuckin C, Sacher JR, Wagner F, Stanulla M, Yuan C, Sicinska E, Giannakis M, Ng K, Dow LE, Gutierrez A.Cancer Discov. 2020 Nov;10(11):1690-1705. doi: 10.1158/2159-8290.CD-19-1472. Epub 2020 Jul 23. PMID: 32703769; PMCID: PMC7642035.

Supramolecular assembly of GSK3α as a cellular response to amino acid starvationHinze L, Schreek S, Zeug A, Ibrahim NK, Fehlhaber B, Loxha L, Cinar B, Ponimaskin E, Degar J, McGuckin C, Chiosis G, Eckert C, Cario G, Bornhauser B, Bourquin JP, Stanulla M, Gutierrez A. Mol Cell. 2022 Aug 4;82(15):2858-2870.e8. doi: 10.1016/j.molcel.2022.05.025. Epub 2022 Jun 21. PMID: 35732190; PMCID: PMC9357031.

GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells. Loxha L, Ibrahim NK, Stasche AS, Cinar B, Dolgner T, Niessen J, Schreek S, Fehlhaber B, Forster M, Stanulla M, Hinze L. Int J Mol Sci. 2023 Aug 26;24(17):13260. doi: 10.3390/ijms241713260. PMID: 37686063; PMCID: PMC10488213.