Prostate cancer is the most common cancer in men and is the third leading cause of cancer deaths. The major problems with this cancer are the absence of a marker of aggressiveness and resistance to treatment. Indeed, there is currently no marker to predict the aggressiveness of this cancer, which kills more than 8000 people per year in France. Our laboratory is interested in studying the molecular and cellular mechanisms involved in the formation of metastases and resistance to treatments.

The fate of tumor cells depends on their microenvironment and the exposure to environmental factors. More generally, cancer cells adapt to their complex ecosystem to sustain proliferation and dissemination. This adaptation requires the regulation of metabolic pathways that promote cell survival, motility, invasiveness and tumor angiogenesis. These capacities involve active communications between tumor cells and their environment regulated by physicochemical variables: nutrients, oxygen concentration (Hypoxia), hormones, and pH. Our team project encompasses the study of cancer cell metabolism as well as interference of endocrine disruptors on cancer progression.

Projects

People
F. BOST

F. BOSTResearch Director
Mail frederic.bost@univ-cotedazur.fr

Cancer cells have a different metabolism than normal cells. They reprogram their metabolism to meet bioenergetic and biosynthetic demands in order to proliferate and invade surrounding tissues. Several studies have shown that metabolic disruptors can slow down tumor growth. Our team was one of the first to demonstrate that metformin, a drug initially prescribed for type 2 diabetes, targets mitochondrial metabolism and induces energy stress in prostate cancer cells. We have shown that metformin slows tumor growth and significantly reduces metastasis. More recently, we have shown that PGC-1 alpha, a transcription factor coactivator, regulates polyamine synthesis and tumor cell aggressiveness. Our research project is to better understand how, by interfering with cellular metabolism, we can target the prostate cancer cell to identify new therapeutic targets.

People
F. BOST

F. BOSTResearch Director
Mail frederic.bost@univ-cotedazur.fr

People
P. Peraldi

P. PeraldiResearcher
Mail Pascal.Peraldi@unice.fr

People
A. Belaid

A. BelaidPost-doctoral fellow
Mail amine.belaid@univ-cotedazur.fr

People
M. Kahi

M. KahiPhD student
Mail Michel.KAHI@univ-cotedazur.fr

People
A. Mazzu

A. MazzuResearch engineer
Mail Abigail.Mazzu@unice.fr

JM. FerreroUniversity Professor - Hospital Practitioner (PU-PH)
Mail jean-marc.ferrero@nice.unicancer.fr

People
N. Mazure

N. MazureResearch Director
Mail nathalie.mazure@univ-cotedazur.fr

C3M

Our team has identified a novel and compelling hypoxia-inducible factor (HIF)- and TP53/TP73-dependent molecular mechanism that involves direct contact between mitochondria and endolysosomes in cancer cells (breast, colon, kidney and lung cancers). This cross-contact involves enlarged mitochondria, exhibiting mitochondrial cristae remodeling, and truncation of the C-terminal voltage-dependent mitochondrial anion channel (VDAC1 to VDAC1-ΔC) by lysosomal peptidases (Legumain-LGM) in hypoxia. This results in increased metabolic regulation of both oxidative phosphorylation (OXPHOS) and glycolysis and increased resistance to chemotherapy. With its three isoforms, VDAC1, 2, and 3, the channel family constitutes the most abundant pore-forming proteins in the mitochondrial outer membrane (MOM) where they control the flow of ADP, ATP, ions, respiratory substrates, and metabolites through the organelle. By binding to VDAC, several cytoplasmic and cytoskeletal proteins, including tubulin, modulate MOM permeability and thus control a wide variety of mitochondrial functions and probably the response to chemotherapy. Aberrant VDAC expression or function has been reported in many tumors, indicating that targeting VDAC is of therapeutic importance for cancer treatment.
We have shown that the hypoxia-induced cleaved form of VDAC1 (i.e., VDAC1-ΔC) is a critical regulator of glycolysis and ciliogenesis, as the conversion of VDAC1 to VDAC1-ΔC correlates with the loss of primary cilium (PC) and increased glycolysis and mitochondrial respiration. Our studies demonstrate that VDAC1-ΔC reprograms PC-deficient cells to utilize more metabolites (i.e. lactate, mannitol, fructose, etc.) promoting cell growth in a hypoxic microenvironment.

People
N. Mazure

N. MazureResearch Director
Mail nathalie.mazure@univ-cotedazur.fr

J. ContentiPhD student
Mail contenti.j@chu-nice.fr

People
Y. Guo

Y. GuoPhD student
Mail yingbo.guo@etu.univ-cotedazur.fr

S. PengPhD student
Mail siyong.peng@etu.univ-evry.fr

People
C. Hinault

C. HinaultUniversity Lecturer - Hospital practitioner (MCU-PH)
Mail Charlotte.Hinault@unice.fr

People
N. Chevalier

N. ChevalierUniversity Professor - Hospital Practitioner (PU-PH)
Mail Nicolas.Chevalier@unice.f

Endocrine-disrupting chemicals (EDCs) are a heterogeneous category of environmental pollutants mainly produced by the chemical industry: pesticides, plastics, pharmaceuticals, paints, glues, etc. Among EDCs, persistent organic pollutants (POPs) are a major source of concern for human health; they are persistent in the environment for several decades and, due to their lipophilic nature, they are bioaccumulative in organisms, particularly in adipose tissue (AT). Although the AT initially plays a protective role by storing these EDCs, the EDCs can cause a modification of the adipose secretome, and be released in the body, especially after weight loss. These changes can have a negative impact on the body, and on the development of certain hormone-sensitive cancers, well beyond the initial exposure period. Our overall objective is to characterize the modifications induced by EDCs on the adipose secretome, and to determine their impact on the proliferation of prostate cells. POPs are grouped into five categories: polychlorinated dibenzoparadioxins (PCDDs) and polychlorinated dibenzofurans (PCBFs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCs) (which have been banned since 1970 because of their toxicity), polybrominated flame retardants (PBDEs) and perfluorooctane derivatives (PFOS and PFOAs) found in non-stick coatings. As some of these POPs have a hormonally-mimetic activity, the IARC (International Agency for Research on Cancer) has suggested a very probable role of exposure to these POPs in the occurrence and development of hormone-sensitive cancers: thyroid, prostate, testis, breast, and ovary. However, the exact risk of POP exposure remains difficult to estimate and quantify.

People
C. Hinault

C. HinaultUniversity Lecturer - Hospital practitioner (MCU-PH)
Mail Charlotte.Hinault@unice.fr

People
N. Chevalier

N. ChevalierUniversity Professor - Hospital Practitioner (PU-PH)
Mail Nicolas.Chevalier@unice.f

P. Caroli-BoscProblème identifiant sur la fonction
Mail philippe.cb@hotmail.f

28th CHO meeting (Organization)

From 12h to 15th October 2022 - Presqu'île de Giens (France)

https://cho2022.sciencesconf.org/

EACR Cancer Metabolism

From 11th to 13th october 2022  - Bilbao (Spain)

https://www.eacr.org/conference/cancermetabolism2022/introduction

Cell Symposia : Multifaceted Mitochondria

From 6th to 8th November 2022 - Seville (Spain)

https://www.cell-symposia.com/mitochondria-2022/

Annual congress of the GDR 3697 Micronit & French Society Tumor Microenvironment

From 5th to 7th December 2022 - Fréjus (France)

https://www.cancer-fstm.fr/

Patents

Patent Number : Patent Number: N° 19 305 179.4 International patent number : METHODS AND COMPOSITIONS FOR SELECTING A CANCER TREATMENT IN A SUBJECT SUFFERING FROM CANCER

Co-inventors N. Mazure, Lucilla Fabbri Maeva Dufies

Patent Number : Patent Number: N°19305762.7 International patent number : METHODS AND COMPOSITIONS FOR SELECTING A CANCER TREATMENT IN A SUBJECT SUFFERING FROM CANCER

Co-inventors N. Mazure, Lucilla Fabbri Maeva Dufies

Show all patents