Luca Lignitto, PhD
Group Leader
Career summary
Throughout my career, I have been interested in the molecular mechanisms underlying the degradation of proteins controlled by the Ubiquitin-Proteasome System (UPS). For the last 14 years, I specialized in the study of E3 ubiquitin ligases, identifying their proteolytic substrates and defining the pathophysiological relevance of their degradation. For my investigations I acquired extensive expertise in a wide range of experimental methods of molecular biology, biochemistry, proteomics, genomics, and mouse models. During my PhD training in the lab of Dr. Antonio Feliciello at the University of Naples “Federico II” in Italy, I dissected the molecular machinery mediating the cross-regulation between the cyclic AMP signaling pathway and the UPS (Lignitto et al., Nature Cell Biol., 2011). As a postdoc, first, in my graduate student lab, and afterwards at New York University (NYU) in the USA, I focused my studies on the UPS-regulated signaling networks underpinning oncogenesis (Lignitto et al., Nature Commun., 2013) (Lignitto et al., Cell, 2019). In particular, during my postdoc in the lab of Dr. Michele Pagano at NYU, I uncovered the existence of a molecular network that links mutations of the oxidative stress pathway to alterations of the heme signaling and UPS-mediated protein degradation, which ultimately promotes oncogenesis. Currently, I am a Group Leader at the Marseille Cancer Research Centre (CRCM) and at the Centre national de la recherche scientifique (CNRS) in Marseille. My laboratory focuses on understanding how heme signaling and oxidative stress regulate cellular physiology and cancer pathogenesis. Our long-term goal is to identify new therapeutic approaches for cancer patients harboring alterations of the heme-oxidative stress pathway.
Luca Lignitto, PhD
Group Leader
Career summary
Throughout my career, I have been interested in the molecular mechanisms underlying the degradation of proteins controlled by the Ubiquitin-Proteasome System (UPS). For the last 14 years, I specialized in the study of E3 ubiquitin ligases, identifying their proteolytic substrates and defining the pathophysiological relevance of their degradation. For my investigations I acquired extensive expertise in a wide range of experimental methods of molecular biology, biochemistry, proteomics, genomics, and mouse models. During my PhD training in the lab of Dr. Antonio Feliciello at the University of Naples “Federico II” in Italy, I dissected the molecular machinery mediating the cross-regulation between the cyclic AMP signaling pathway and the UPS (Lignitto et al., Nature Cell Biol., 2011). As a postdoc, first, in my graduate student lab, and afterwards at New York University (NYU) in the USA, I focused my studies on the UPS-regulated signaling networks underpinning oncogenesis (Lignitto et al., Nature Commun., 2013) (Lignitto et al., Cell, 2019). In particular, during my postdoc in the lab of Dr. Michele Pagano at NYU, I uncovered the existence of a molecular network that links mutations of the oxidative stress pathway to alterations of the heme signaling and UPS-mediated protein degradation, which ultimately promotes oncogenesis. Currently, I am a Group Leader at the Marseille Cancer Research Centre (CRCM) and at the Centre national de la recherche scientifique (CNRS) in Marseille. My laboratory focuses on understanding how heme signaling and oxidative stress regulate cellular physiology and cancer pathogenesis. Our long-term goal is to identify new therapeutic approaches for cancer patients harboring alterations of the heme-oxidative stress pathway.
Luca Lignitto, PhD
Group Leader
Career summary
Throughout my career, I have been interested in the molecular mechanisms underlying the degradation of proteins controlled by the Ubiquitin-Proteasome System (UPS). For the last 14 years, I specialized in the study of E3 ubiquitin ligases, identifying their proteolytic substrates and defining the pathophysiological relevance of their degradation. For my investigations I acquired extensive expertise in a wide range of experimental methods of molecular biology, biochemistry, proteomics, genomics, and mouse models. During my PhD training in the lab of Dr. Antonio Feliciello at the University of Naples “Federico II” in Italy, I dissected the molecular machinery mediating the cross-regulation between the cyclic AMP signaling pathway and the UPS (Lignitto et al., Nature Cell Biol., 2011). As a postdoc, first, in my graduate student lab, and afterwards at New York University (NYU) in the USA, I focused my studies on the UPS-regulated signaling networks underpinning oncogenesis (Lignitto et al., Nature Commun., 2013) (Lignitto et al., Cell, 2019). In particular, during my postdoc in the lab of Dr. Michele Pagano at NYU, I uncovered the existence of a molecular network that links mutations of the oxidative stress pathway to alterations of the heme signaling and UPS-mediated protein degradation, which ultimately promotes oncogenesis. Currently, I am a Group Leader at the Marseille Cancer Research Centre (CRCM) and at the Centre national de la recherche scientifique (CNRS) in Marseille. My laboratory focuses on understanding how heme signaling and oxidative stress regulate cellular physiology and cancer pathogenesis. Our long-term goal is to identify new therapeutic approaches for cancer patients harboring alterations of the heme-oxidative stress pathway.
Luca Lignitto, PhD
Group Leader
Career summary
Throughout my career, I have been interested in the molecular mechanisms underlying the degradation of proteins controlled by the Ubiquitin-Proteasome System (UPS). For the last 14 years, I specialized in the study of E3 ubiquitin ligases, identifying their proteolytic substrates and defining the pathophysiological relevance of their degradation. For my investigations I acquired extensive expertise in a wide range of experimental methods of molecular biology, biochemistry, proteomics, genomics, and mouse models. During my PhD training in the lab of Dr. Antonio Feliciello at the University of Naples “Federico II” in Italy, I dissected the molecular machinery mediating the cross-regulation between the cyclic AMP signaling pathway and the UPS (Lignitto et al., Nature Cell Biol., 2011). As a postdoc, first, in my graduate student lab, and afterwards at New York University (NYU) in the USA, I focused my studies on the UPS-regulated signaling networks underpinning oncogenesis (Lignitto et al., Nature Commun., 2013) (Lignitto et al., Cell, 2019). In particular, during my postdoc in the lab of Dr. Michele Pagano at NYU, I uncovered the existence of a molecular network that links mutations of the oxidative stress pathway to alterations of the heme signaling and UPS-mediated protein degradation, which ultimately promotes oncogenesis. Currently, I am a Group Leader at the Marseille Cancer Research Centre (CRCM) and at the Centre national de la recherche scientifique (CNRS) in Marseille. My laboratory focuses on understanding how heme signaling and oxidative stress regulate cellular physiology and cancer pathogenesis. Our long-term goal is to identify new therapeutic approaches for cancer patients harboring alterations of the heme-oxidative stress pathway.
Luca Lignitto, PhD
Group Leader
Career summary
Throughout my career, I have been interested in the molecular mechanisms underlying the degradation of proteins controlled by the Ubiquitin-Proteasome System (UPS). For the last 14 years, I specialized in the study of E3 ubiquitin ligases, identifying their proteolytic substrates and defining the pathophysiological relevance of their degradation. For my investigations I acquired extensive expertise in a wide range of experimental methods of molecular biology, biochemistry, proteomics, genomics, and mouse models. During my PhD training in the lab of Dr. Antonio Feliciello at the University of Naples “Federico II” in Italy, I dissected the molecular machinery mediating the cross-regulation between the cyclic AMP signaling pathway and the UPS (Lignitto et al., Nature Cell Biol., 2011). As a postdoc, first, in my graduate student lab, and afterwards at New York University (NYU) in the USA, I focused my studies on the UPS-regulated signaling networks underpinning oncogenesis (Lignitto et al., Nature Commun., 2013) (Lignitto et al., Cell, 2019). In particular, during my postdoc in the lab of Dr. Michele Pagano at NYU, I uncovered the existence of a molecular network that links mutations of the oxidative stress pathway to alterations of the heme signaling and UPS-mediated protein degradation, which ultimately promotes oncogenesis. Currently, I am a Group Leader at the Marseille Cancer Research Centre (CRCM) and at the Centre national de la recherche scientifique (CNRS) in Marseille. My laboratory focuses on understanding how heme signaling and oxidative stress regulate cellular physiology and cancer pathogenesis. Our long-term goal is to identify new therapeutic approaches for cancer patients harboring alterations of the heme-oxidative stress pathway.
Unravel the mechanisms linking alteration of the heme-oxidative stress pathway to lung tumor development and progression
In cancers, heme signaling can be deregulated through alteration of the oxidative stress homeostasis. Oxidative stress is induced by elevated intracellular levels of reactive oxygen species (ROS). ROS play pleiotropic roles in tumorigenesis; while ROS are pro-tumorigenic, high ROS levels are cytotoxic. Cancer cells exhibit aberrant redox homeostasis that allows them to thrive under conditions of high oxidative burden. Specifically, hyperproliferation of tumor cells is accompanied by high ROS production, however, cancer cells accommodate high ROS levels by increasing their antioxidant status to optimize ROS-driven proliferation, while at the same time avoiding ROS thresholds that would trigger senescence and apoptosis.
To maintain oxidative homeostasis and sustain tumor growth, ~30% of non-small cell lung cancers (NSCLCs) increase the transcription of antioxidant genes by acquiring either stabilizing mutations in the transcription factor NRF2 (the NFE2L2 gene product) or by selecting for Loss-of-Function (LOF) mutations in its negative regulator, KEAP1. NRF2 increases the cells antioxidant defense by upregulating, among the others, genes involved in glutathione and NADPH metabolism as well as genes involved in the maintenance of signaling heme homeostasis. Excess of signaling heme is cytotoxic since it catalyzes the formation of ROS through Fenton reaction, resulting in oxidative stress. In turn, oxidative stress elicits heme release from heme-binding proteins, thus amplifying heme toxicity. NRF2 avoids the self-amplifying, pro-oxidant effects of signaling heme by inducing the transcription of genes regulating heme homeostasis, among which heme-oxygenase-1 (HO-1), the enzyme degrading signaling heme.
Using CRISPR/Cas9 in KP (KRASG12D; p53-/-) GEMM (i.e., genetically engineered mouse model), we recently discovered that LOF mutations of KEAP1 in NSCLC promote tumor progression via alteration of the heme signaling. Our findings contributed to identify novel vulnerabilities in lung cancer patients harboring alteration of the KEAP1/NRF2 pathway, and demonstrated that drugs targeting the heme pathway can be effectively used as therapeutics to inhibit the progression of these cancers. However, given that the heme signaling potentially targets multiple cellular pathways, effectors and substrates, the role of heme pathway in these cancers remains to be defined.
Today, our laboratory aims to achieve a deep understanding of the mechanisms linking alterations of the heme signaling to cancer development, and, in particular, to KEAP1/NRF2 mutant lung tumors pathogenesis. Our ultimate goal is to identify genotype-specific cancer vulnerabilities which may pave the road for the design of new personalized genotype-based therapies.
To pursue our goals, we focus on:
1. Understanding how KEAP1/NRF2 mutations in lung cancer impact on the heme-UPS regulated protein degradation. For our analyses, we use orthogonal approaches combining biochemistry, proteomics and mouse genetics to identify the heme-UPS substrates which are deregulated in cancer and to determine their role in the mechanisms of tumorigenesis.
2. Investigating how alteration of heme-BACH1 impacts on the biology of KEAP1/NRF2 mutant lung cancer models harboring mutations in additional signaling pathways that frequently co-occur in patients. To replicate these specific lung cancer patient genotypes, we use CRISPR/Cas9. Currently, we are generating lung cancer models harboring mutations in the oncogene KRAS and on the tumor suppressor LKB1; these two genes are mutated in ~30% (for KRAS) and ~45% (for LKB1) of the lung cancer patients with KEAP1 lesions, respectively. We use genomic approaches to identify the targets of the heme-BACH1 pathway in these tumor models, and molecular biology together with mouse genetics to understand how alteration of these targets influence tumor evolution.