Project acronym CombaTCancer
Project Rational combination therapies for metastatic cancer
Researcher (PI) Anna Obenauf
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Summary
Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym NPC-BUILD
Project The Nuclear Pore Basket – Functional Architecture of a Membrane Remodeling Machine
Researcher (PI) Alwin KÖHLER
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary Nuclear pore complexes (NPCs) are gatekeepers at the nuclear envelope, mediating traffic between the nucleus and cytoplasm. Unlike simpler protein channels that insert into a single lipid bilayer, NPCs can remodel the outer and inner nuclear membranes to form a specialized pore in the nuclear envelope. High-resolution models of the symmetric NPC core have transformed our understanding of NPC architecture. In contrast, we know little about the NPC basket, a prominent structure on the nucleoplasmic side of NPCs. This lack of knowledge is salient, because the basket impacts on transport, DNA repair, and chromatin activity. Notably, the basket was recently found to play a key role in shaping the nuclear membrane, which is critical for NPC biogenesis. Studying the NPC basket is challenging because of its size, intricate architecture, structural flexibility and embedding in a membrane. Yet, knowledge of the architecture of the NPC basket is central to understanding how it influences gene expression, and operates in membrane remodeling in synergy with the NPC core. I propose to develop new experimental tools that will enable a structural analysis of the basket in its membrane environment. This will provide unprecedented insight into the function of this enigmatic part of the NPC.
Summary
Nuclear pore complexes (NPCs) are gatekeepers at the nuclear envelope, mediating traffic between the nucleus and cytoplasm. Unlike simpler protein channels that insert into a single lipid bilayer, NPCs can remodel the outer and inner nuclear membranes to form a specialized pore in the nuclear envelope. High-resolution models of the symmetric NPC core have transformed our understanding of NPC architecture. In contrast, we know little about the NPC basket, a prominent structure on the nucleoplasmic side of NPCs. This lack of knowledge is salient, because the basket impacts on transport, DNA repair, and chromatin activity. Notably, the basket was recently found to play a key role in shaping the nuclear membrane, which is critical for NPC biogenesis. Studying the NPC basket is challenging because of its size, intricate architecture, structural flexibility and embedding in a membrane. Yet, knowledge of the architecture of the NPC basket is central to understanding how it influences gene expression, and operates in membrane remodeling in synergy with the NPC core. I propose to develop new experimental tools that will enable a structural analysis of the basket in its membrane environment. This will provide unprecedented insight into the function of this enigmatic part of the NPC.
Max ERC Funding
2 178 488 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym POLICE
Project The PIDDosome in Centrosome and Ploidy-Surveillance
Researcher (PI) Andreas VILLUNGER
Host Institution (HI) MEDIZINISCHE UNIVERSITAT INNSBRUCK
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood.
We recently demonstrated that the “PIDDosome” complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome.
This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define
(i) the relevance of the PIDDosome in aneuploidy tolerance of cancer
(ii) the role of the PIDDosome in controlling sterile inflammation and immunity
(iii) the PIDDosome as a key-regulator of organ development and regeneration
POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Summary
Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood.
We recently demonstrated that the “PIDDosome” complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome.
This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define
(i) the relevance of the PIDDosome in aneuploidy tolerance of cancer
(ii) the role of the PIDDosome in controlling sterile inflammation and immunity
(iii) the PIDDosome as a key-regulator of organ development and regeneration
POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Max ERC Funding
2 355 000 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
