Title: Patient-derived models for intratumor functional heterogeneity and its implications for personalized medicine

Project Coordinator:
Kuo Ming-Liang (Taiwan) College of Life Sciences, National Taiwan University, successively Yang Pan-Chyr (Taiwan) National Taiwan University Taipei

Project Partners:
Blanpain Cédric (Belgium) Interdisciplinary Research Institute (IRIBHM) Université Libre de Bruxelles
Mehlen Patrick (France) Centre Léon Bérard, University of Lyon, Lyon
Sandro De Falco (Italy) Institute of Genetics and Biophysics “A. BuzzatiTraverso", Department of Biomedical Sciences, CNR
Yang Pan-Chyr (Taiwan) National Taiwan University Taipei

Project Abstract:
a. Intratumoural heterogeneity plays a critical role in tumour evolution and may strongly impact personalized medicine. Within a tumor, genetic heterogeneity among malignant cells together with cancer stem cells (CSC) and tumor microenvironment plasticity, are the drivers of functional heterogeneity that strongly impact on patients’ outcomes. The basis of the beFIT project is to better understand the tight link between CSC and the niche controlling CSC to develop a strong rational for innovative anti-CSC-based therapies.
b. In the complex tumour ecosystem, the tumour microenvironment may be a driving force to control tumour plasticity, heterogeneity, and cancer stemness. We hypothesize that targeting CSCs and their niche will be usefull to overcome drug resistance, prevent recurrence, and possibly promotes cancer eradication.
c. Using patient-derived models and focusing the whole project on lung cancer, the leading cause of cancer-related death worldwide, our specific aims are (i) to investigate CSC molecular signatures and develop animal and mathematical models to determine CSC and microenvironment respective roles in heterogeneity and drug response, (ii) to understand the role of the microenvironment and more specifically of cancer-associated fibroblasts (CAF), endothelial cells and immune cells in CSC plasticity and survival, (iii) to use these models and knowledge to propose an extension cohort for a phase I clinical trial targeting lung CSC.
d. Based on the patient derived models (PDX, CTC, CSC/CAF) from liquid biopsies (pleural effusion or blood) or tissue biopsies at different time points or nodules prospectively collected in patients with lung adenocarcinoma, the evolution and heterogeneity of CSC characteristics over time and across disease progression will be studied. Comprehensive and deep sequencing of genomic/epigenomic approaches with functional phenotypes (cancer stemness, drug-resistance, EMT, angiogenesis) will be generated to examine the heterogeneity of each clone in primary CSC cultures and PDX. Also, the tumour evolution will be evaluated under different microenvironmental stresses, including therapeutic (chemo-, and radiation therapy-) or non-therapeutic (hypoxia, pH, carcinogens). We will evaluate the impact and potential therapeutic interventions of intratumour heterogeneity and cancer stemness on clinical outcomes, including the latter analysis will pave the road to the first-in-human phase I clinical trial using a netrin-1 monoclonal antibody specifically affecting CSC.
e. Through the tight collaboration between experts in the fields of CSC (Taiwan, Belgium), tumour cell plasticity (France), microenvironment (Italy), drug development and clinical research (Taiwan and France), this project will establish a state-of-the art platform for studying the functional intratumour heterogeneity that may significantly impact patients treatment and outcome.

Final Summary:
This “BeFIT” project focuses on the heterogeneity within intra-patient heterogeneity, which could be major driving force for the cancer stemness, drug-resistance and metastasis. We believe that functional heterogeneity plays the role for the adaptation of the tumor under dynamic and stressful micro-environmental conditions and/or changing its malignant and survival potential under therapeutic stress. Based on this, our groups both have tried to developed the patient-derived xenograft (PDX) model on studying the inter-/intra-tumoral heterogeneity and tumor evolution; also, Taiwan’s team work with Dr. Patrick’s team (French) and Italy group on developing and studying the heterogeneity of cancer cells in the CSCs/CAFs co-culture system under different environmental stresses, including hypoxia and acidic condition. We have identified several important key regulators of cancer stemness, drug resistance, and immune checkpoint regulators that are significantly modulated in tumor heterogeneity and evolution under the stress conditionings and could be benefit for the anti-cancer precision medicine in the coming future.


(Project funded under JTC 2014)