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Page 4 of 27 J Cancer Metastasis Treat 2019;5:5 I http://dx.doi.org/10.20517/2394-4722.2018.108

reprograming, and, thus, targeting MCT1 in both tumour cells and brain endothelial cells may be a
promising therapeutic strategy for the treatment of GBM.

4. Metformin: toward drugging the metabolic control of epigenetics in cancer

Javier A. Menendez

Catalan Institute of Oncology-Girona Biomedical Research Institute, Girona 17007, Spain.

There is a growing appreciation that metabolic rewiring affects the epigenome in a manner that facilitates
cancer formation, progression, and therapeutic resistance. An improved understanding of how the interplay
between cell metabolism and the epigenome regulates major cell fate decisions such as cell differentiation,
proliferation, and/or cell death, might radically amend the way we prevent and treat cancer. Metformin,
a biguanide derivative that has long been a cornerstone in the treatment of type 2 diabetes (T2D), could
help to accelerate the development of novel strategies capable of therapeutically tuning the metabolism-
epigenome axis to battle cancer. This talk will summarize the most recent evidence collected in our
laboratory unraveling the capacity of metformin to operate as a poly-therapeutic agent targeting the biologic
machinery in charge of the metabolic recoding of cancer epigenetics. On the one hand, metformin can
alter the abundance of mitochondrial metabolites that are substrates of chromatin-modifying enzymes
(e.g., acetyl-CoA for histone acetyltransferases) by altering the energy status of the cell downstream of its
primary inhibitory action on mitochondrial respiratory complex I. On the other hand, biocomputational
approaches based on artificial intelligence coupled to experimental validation reveal that metformin is: (1)
a direct SIRT1-activating compound that improves the catalytic efficiency of SIRT1-mediated deacetylation
+
in cancer-prone conditions of low NAD ; and (2) a potent regulator of S-adenosyl methionine - mediated
methylation reactions via direct and specific inhibition of a central reaction of the folate cycle, namely
the conversion of serine to glycine by the mitochondrial serine hydroxymethyltransferase 2 enzyme. The
biguanide metformin, which, sixty years after its introduction in Europe as a first-line therapeutic for
T2D, may now been seen as an archetypal compound aiming at drugging the metabolism-epigenome
axis in cancer.

5. PIK3C2G loss promotes pancreatic cancer development and metabolic rewiring

Miriam Martini, Maria Chiara De Santis, Edoardo Ratto, Luca Gozzelino, Abhishek Uttamrao
Derle, Paolo Ettore Porporato, Emilio Hirsch

Molecular Biotechnology Center, Dip of Mol Biotechnology and Health Science, Torino 10126, Italy.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer across the world, with
incidence equaling mortality. A wealth of studies have identified the PI3K/mTOR axis as an important
player in PDACs, impacting on tumor growth and metabolism. In particular, PI3K-C2γ, differently from
other PI3Ks, is mainly expressed in the pancreatic tissue where it plays a critical role in controlling glucose
metabolism.

Experimental model: Mouse model of PDAC (K-RASG12D/Trp53R172H/CrePdx1) was crossed with mouse
strain lacking PI3K-C2γ expression. Mice were weekly followed for survival, tumor appearance and growth.
Tumor lesions were evaluated by histopathological and immunofluorescence analysis. Functional in vitro
and in vivo experiments were performed.