Role of purine-converting enzymes and inflammasome as new diagnostic, prognostic and therapeutic markers in hypoxic breast cancer
Progetto Cancer is a complex multifactorial disease where the tumor
microenvironment (TME) is emerging as a crucial player in determining a
favorable or hostile milieu for cancer cell survival. Purines and their
metabolizing enzymes are involved in numerous physiological and
pathological conditions, including cancer and inflammation, thus garnering
increasing interest as therapeutic target in clinical practice. Several purineconverting
enzymes, namely 5’-nucleotidase (N-II)/CD73 and purine
nucleoside phosphorylase (PNP), are particularly elevated in highly invasive
cancers, where they positively correlate with tumor progression and
metastasis. However, the mechanisms through which CD73 or PNP would
induce cancerogenesis are not fully understood, and their role is still
controversial.
Therefore, this project aims to define the role of CD73 and PNP as new
diagnostic, prognostic and therapeutic tools in oncology. Enzyme altered
expression/activity will be assessed in human breast cancers (BC) by stateof-
the-art technologies (including proteome profiling and high-throughput
unbiased post-translational modification assessment by differential
proteomics, CRISPR/Cas9-based gene editing, RNA interference and gene
overexpression). The expression/activity of these purine-converting
enzymes will be evaluated in relation to hypoxic conditions and
inflammasome activation, both accounting for the activation of pro-survival
pathways in TME, hence promoting tumor growth and invasion.
The mechanics of the regulation as well as the impact of these signaling
complexes on tumor development and malignant progression from early to
advanced stages will be investigated at genomic, transcriptomic and
proteomic levels in BC cell lines, and then extended to body fluids collected
from cancer patients before and after chemotherapy. The proposed project
will also explore the impact of radio- and chemotherapy on PNP and CD73
levels in BC patients.
We expect to define the signaling network between purine metabolism, HIF-
1α, and NLP3 inflammasome activation in BC, therefore providing new hints
for the generation of novel combination strategies targeting BC progression
and overcoming chemoresistance.