Title: TArgeting Colon Tumor Initiating Cell heterogeneity
Jean Paul MEDEMA (Netherlands) Academic Medical Center / LEXOR, Center of Exp Molecular Medicine
Ann ZEUNER (Italy) Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome
Hanno GLIM (Germany) Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ) Heidelberg
Hector G. PALMER (Spain) Stem Cells and Cancer Laboratory Vall d´Hebrón Institute of Oncology - VHIO, Barcelona
Livio TRUSOLINO (Italy) Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute FPO, IRCCS Candiolo, Torino
Tumor heterogeneity poses a formidable challenge in our understanding of tumor biology and therapy efficacy. Complex clonal patterns, patient-to-patient variations and microenvironmental differences all underpin tumor heterogeneity and render the study of this disease extremely difficult. Moreover, it has become increasingly clear that intra-tumor heterogeneity is a direct result of a hierarchical organization that is highly reminiscent to normal tissue organization with a minor fraction of tumor initiating cells (TICs) at the apex. TICs form the root of the tumor, are instructed by the microenvironment and can very efficiently give rise to tumor phenocopies upon injection in mice. Importantly, recent evidence in colorectal cancer (CRC) by our team members has shown that this TIC population displays a further heterogeneity that is dictating therapy efficacy. These findings indicate that a subset of quiescent cells can be identified that, upon re-activation, can regenerate the complete tumor. More importantly, these cells are extremely therapy resistant and effectively colonize distant metastatic sites.
This proposal therefore builds on the hypothesis that TIC heterogeneity is a major culprit in CRC progression and resistance to therapy and that targeting quiescent TICs is of crucial importance for therapy success. To increase our understanding of the (epi-)genetic wiring of these quiescent TICs, to validate and circumvent their role in therapy success and to define their relation to patient outcome the program has three main aims that together will have a major impact on CRC treatment.
Aim1: Identification of unique markers, pathways and resistance mechanisms that define TIC heterogeneity.
Within this part we will use our unique models and specialties to isolate different TIC populations and perform deep-sequencing, epigenetic and RPPA protein analysis to determine the wiring of different TICs. In addition, we will use our in house developed protocols to screen for therapy resistance and to identify novel combinatorial therapies.
Aim2: Identification of genetic heterogeneity within TICs and validation of markers and therapies to target quiescent TICs. Using genetic tracing and label retention techniques, the identified markers and pathways will be validated in a large and unique panel of CRC PDX models. In addition, the combination therapies will be studied in xenotrials and the genetic variation that underlies escape will be analyzed.
Aim3: Linking of quiescent TICs to patient outcome and analyzing novel therapeutic approaches.
Data derived from aim1/2 will be validated in retrospective patient sets as well as in ongoing clinical phase I/II trials that study novel targeted agents in CRC. Combined these studies are expected to provide validated tools to identify and target quiescent TICs, which through the unique link to clinical trials will provide a rapid translation of our findings to clinical practice.
TACTIC aims were to understand how a subset of tumour cells called tumour initiating cells (TICs) are involved in the failure of therapy. TICs are known to resist therapy and this is especially the case when they enter a state of dormancy called quiescence. In the last years we have shown that several specific markers can be used to identify quiescent TICs and that in some cases these pathways are induced by therapy. Importantly, we have also found that this provides a window of opportunity as it allows for selective combination therapies that are based on these activated pathways.
Next to the functional changes that occur in quiescent TICs we have shown that qTICs are present in different subclones and do not define a subclonal feature. Translation of these finding towards patient samples and novel therapies in current being pursued. Several of the markers that we identified can be used to predict recurrence after therapy pointing to a role of qTICs in recurrence. Pre-clinical studies in mice have provided support for the combination therapy that would target qTICs and will allow further clinical development of these treatments.
(Project funded under JTC 2014)