Unrafeling the role of autophagy in cutaneous malignant melanoma.

Patrizia
14.00






In advanced cancer, autophagy, an evolutionary
conserved catabolic process, has been reported to support tumor progression.
Based on this premise,clinical trials have been initiated to evaluate the
possible benefitof the autophagy blocker chloroquine (CQ) for the treatment of
advanced cancers, with promising results. However, studies addressing the
responsible mechanism of action of CQ are scarce and the effect of CQ cannot
always be reproduced by knocking down key autophagy genes. Moreover,
preclinical studies addressing the role of autophagy inhibition either
pharmacological or genetic- mainly focus on tumor cells themselves, although
the tumor micro-environment is emerging as an important determinant in tumor
progression and therapy resistance. Therefore, in this study we set out to
elucidate the mechanisms underlying theeffects of CQ in anti-cancer therapy as
well as to compare the impact of chloroquine or genetic inhibition of autophagy
on the tumor-microenvironment.

Here, using 2 transplantable mouse melanoma models, we
report that in vivo knockdown of the
key autophagy gene Atg5 in the cancer cells or knockout of ATg5 in the
endothelial cells, significantly decreased tumor growth, whereas the effect of
CQ on tumor growth was dependent on the cancer cell line and the dose
administered. Intriguingly, detailed analysis of the tumors revealed that CQ
had a striking effect on the tumor micro-environment, which was not phenocopied
by reducing autophagic flux in the cancer cells (shRNA Atg5) or in the
endothelial cells (shRNA targeting ATg5 in
vitro and an endothelial-cell specific Atg5 knockout mouse model in vitro). CQ treated tumors were less
hypoxic and necrotic, and displayed reduced invasiveness and metastasis. CQ
treatment also significantly improved the response to chemotherapy. We found
that the beneficial effects exerted by CQ on the tumor micro-environment were
mediated by its ability to ameliorate tumor vessel structure and function, a
phenomenon described as tumor vessel normalization. At the mechanistic level, the
vascular normalizing effects of CQ were ascribed to the unique ability of CQ to
induce a quiescent endothelial cell phenotype by increasing Notch signaling in
the late endosomal compartment. These results provide new insights into the
underlying mechanism of CQ anti-tumoraction and further support the use of CQ
as a new tumor vessel normalization agent in the clinic.



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Keywords:Anti-cancer therapy, Autophagy, Melanoma, Hypoxia, Cell signalling

Disciplines:Dermatology, Morphological sciences, Oncology

Project type:PhD project