Autophagy represents a well conserved self-degradation system critical for cellular homeostasis and survival during stress conditions. In cancer, autophagy plays as ¿double-edge sword¿, in fact it can promote or suppress tumor development, by regulating drug resistance and aggressiveness.
So far, many studies have shown that cytosolic calcium (Ca2+) oscillations are involved in the regulation of autophagic signals. Several data have demonstrated that cancer cells are able to remodel their Ca2+ signalling network and that its disruption contribute to malignant phenotype development. An important role is played by transient receptor potential (TRP) channels which are responsible for ion homeostasis, and their expression has been also associated with tumour progression, metastasis, proliferation and chemoresistance. To date, little is known about their involvement in blood malignancies, especially in chronic myeloid leukaemia (CML), and in autophagy pathway as well. Programmed death ligand 1 (PD-L1) plays a crucial role in cancer, by inhibiting immune response against cancer cell, increasing chemoresistance and relapses. It has been demonstrated that autophagy inhibition prompts PD-L1 expression; moreover, PD-L1 is found to be up regulated in CML.
Therefore, the aim of this study is to investigate in myeloid leukaemia the TRP involvement in autophagy pathway, cancer stem cell and PD-L1 expression through molecular and biochemical approaches by using specific TRP ligands, or modulating TRPs specific expression, in leukemia cell lines treated with conventional drugs.
Chronic myeloid leukaemia (CML) is characterized by incomplete differentiation of hematopoietic stem cells into the adult form with consequent accumulation of immature cells in the bone marrow and peripheral blood. These cells show uncontrolled proliferation, reduced sensitivity to apoptotic signals that promote the growth and selection of a progenitor population known as leukaemia stem cells (LSC). Numerous studies have shown that LSCs themselves are involved in initiation, drug resistance and recurrence of CML. Although good results have been achieved thanks to the introduction of tyrosine kinase (TKI) inhibitors, such as imatinib, nilotinib, dasatinib, bosutinib and ponatinib, into clinical practice, bringing the survival rate to over 90%, for several subjects this treatment must be discontinued or modified due to the development of adverse drug reactions or resistance. For this reason, recent data support the use of mixed therapeutic approaches aimed at considering not only kinase-dependent mechanisms, but also independent ones. In fact, a lot of research is aimed at studying in greater depth new targets expressed exclusively on LSCs.
The main objective is to identify new targets to selectively develop innovative drugs useful for the elimination of leukaemia cells and leukaemia stem cells. In this scenario, we are confident that our study could provide new therapeutical strategies able to affect autophagic pathways and chemoresistance in order to markedly reduce cancer cell survival and evasion from immune system. Attention will be focused on TRP channels, which regulate the traffic of calcium in cells, implicated in cell proliferation and differentiation. Since little is known about their involvement in the development and progression of chronic myeloid leukaemia, this project will clarify the role of TRP, influencing the autophagic pathway, proliferation, drug resistance, cell differentiation and escape processes from immune survival. Autophagy defects alter the determination and differentiation of cell fate and have been implicated both positively and negatively in tumorigenesis. Since growing preclinical evidence suggests that many therapies induce autophagy, targeting this process can improve the effectiveness of cancer therapies (1,2).
Thanks to this study, a new therapeutic strategy to target TRP channels in chronic myeloid cells will be studied. Therefore, a better a better awareness of the TRP-dependent autophagy process and a subsequent interest in the network between immunosuppressive molecules expression and autophagy, allows the acquisition of information useful to improve therapeutic efficacy and to discover new possible therapeutic targets for further pharmacological treatments both as adjuvants and as new healings.
The study on the relationship between autophagy, immunosuppressive molecule expression and TRP expression can provide relevant information on chemoresistance, tumor microenvironment and myeloid leukaemia progression, leading to possible new follow-up targets.
1. Rothe, et al. Int. J. Mol. Sci. 461 2019.
2. Auberger & Puissant. Blood 547-552 2017.