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Research summary

Our group challenges important clinical obstacles in cancer treatment and also presents new knowledge in cancer and insulin signaling biology. Our findings and approaches are novel and if our hypothesis proves to be right we will be able to introduce new targeted treatment strategies to reduce cisplatin resistance in solid cancers.

The target proteins, ASNA1 and GRP94 affect both insulin secretion and cisplatin resistance. Our studies will help to better understand how to reduce cisplatin resistance without reducing insulin secretion as well as increase our knowledge of ASNA1 and GRP94 roles in insulin/IGF signaling (IIS) and insulin secretion.

We have identified a novel target, ASNA1, to increase sensitivity to platinum-based drugs, which can be of major clinical importance. In our Cell paper we showed that ASNA1 is necessary for growth control and insulin secretion. Also, ASNA1 depletion cause increased sensitivity to the platinum drug cisplatin and we generated site directed mutations in ASNA-1 which cause cisplatin sensitivity while insulin secretion was intact.

While other studies biochemically and in vitro have shown that ASNA1 is necessary for post-translational insertion of Tail anchored (TA) proteins into the endoplasmic reticulum (ER) we are the first group to show this in vivo and more important; we have strong indications that ASNA1 has other key functions and that the insulin secretion function of ASNA1 is independent of its role in TA protein handling.

Research tools and resources

We apply an unconventional, innovative and novel approach to perform translational biology studies in cancer with the C. elegans model system. In vivo studies in C. elegans are comparatively time and cost efficient. Confirmatory experiments are then performed in human cancer and insulinoma cell lines. As one of the larger departments in Sweden for cancer surgery we can utilise large patients cohorts and cancer tissue biobanks to validate our hypothesis.

Current group members

Peter Naredi, MD, Professor
Gautam Kao, PhD, Researcher
Johan Bourghardt Fagman, Researcher

Selected publications

1. 
   Jaffee EM., … Naredi P., et al. Lancet Oncol. 11:e653-e706, 2017.
    
2. 
   Norlin, S., Parekh, V., Naredi, P., Edlund, H. Diabetes 65 (1):110-119, 2016.
    
3. 
   Naredi, P., La Quaglia, M. Nature Reviews Clinical Oncology, 12:425-31, 2015.
    
4. 
   Sullivan, R., Peppercorn, J., Sikora, K., Naredi, P., et al. Lancet Oncol 12(10):933-80, 2011.
    
5. 
   Palm, M., Weise, C., Lundin, C., Wingsle, G., Nygren, Y., Björn, E., Naredi, P., Wolf-Watz, M., Wittung-Stafshede, P.  Proc Natl Acad Sci USA 108(17):6951-6, 2011.
    
6. 
   Hemmingsson, O., Kao, G., Still, M., Naredi, P.  Cancer Res 70(24):10321-8, 2010.
    
7. 
   Kao, G., Nordenson, C., Still, M., Rönnlund, A., Tuck, S., Naredi, P. Cell 128:577-87, 2007.
    
8. 
   Agarwala, S., Glaspy, J., O’Day, S., Mitchell, M., Gutheil, J., Whitman, E., Gonzalez, R., Hersh, E., Feun, L., Belt, R., Meyskens, F., Hellstrand, K., Wood, D., Kirkwood, J.M., Gehlsen, K.R., Naredi, P.  J Clin Oncol 20:125-33, 2002.
    
9. Histamine, cimetedin and colorectal cancer.
   Hellstrand, K., Brune, M., Mellqvist, U-H. Naredi, P.  Nature Med 2:364-5, 1996.
    
10. 
    Naredi, P., Heath, D. D., Enns, R. E., Howell, S.B.  J Clin Invest 95:1193-8, 1995.