Project Details
Projekt
SP1: Exploiting tumor cell-intrinsic and -extrinsic processes for boosting gemcitabine sensitivity in ARID1A-deficient PDAC
Applicant
Professorin Dr. Elisabeth Heßmann
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426671079
In the first funding period of the CRU5002, we characterized transcriptional reprogramming processes in ARID1A-deficient pancreatic cancer (PDAC) subtypes and identified autocrine regulation of inflammatory transcription hubs as a pivotal mechanism fostering progression of ARID1A-deficient PDAC. We observed that reprogramming in the context of ARID1A-deficiency is not limited to the ARID1A-deficient epithelial PDAC cell itself, but also effects the composition of the tumor microenvironment. Moreover, findings in pre-clinical PDAC models provided by the CRU5002 revealed increased gemcitabine vulnerability of ARID1A-deficient PDAC. Based on these findings we hypothesize that ARID1A-deficiency orchestrates dynamic cross-talk of the cell-intrinsic and -extrinsic tumor ecosystem in PDAC, thus installing a gemcitabine-susceptible state. In the second funding period, we aim at understanding the transcriptional and cellular reprogramming processes underlying gemcitabine sensitivity of ARID1A-deficient PDAC subtypes. We will utilize the model- and genomic as well as transcriptomic data resources provided by the CRU5002 and take advantage of the MolPAC and Molecular Tumor Board clinical cohorts accessible to the CRU5002 to decipher the predictive value of ARID1A-deficiency for gemcitabine response. Moreover, we seek to understand the transcription nodes and paracrine signaling cues inducing transcriptional and cellular landscape shifts to causally explain the gemcitabine susceptible state of ARID1A-deficient PDAC. To this end, we will combine multilayered transcriptional and epigenomic profiling approaches and single-cell RNA-sequencing technology followed by in vitro and in vivo validation studies. Finally, we aim to identify therapeutic strategies that enable boosting of gemcitabine sensitivity in ARID1A-deficient PDAC subtypes, thus prolonging patient survival. We will consider our mechanistic findings for rationale treatment options, but also elucidate the impact of therapeutic strategies interfering with the metabolome or with treatment concepts particularly efficient in basal-like PDAC subtypes. Finally, we will take advantage of translational PDAC models and of the in vitro PDAC model platform provided by the CRU5002 to assess treatment combination strategies in a highly standardized and unbiased manner. Together, we expect our study to reveal a therapeutic concept tailored to ARID1A-deficient PDAC patients, which has the potential to prolong their progression-free survival under gemcitabine treatment.
DFG Programme
Clinical Research Units
