Defining the Role of Chromatin Remodeling Complexes in Control of Master Transcription Factor Networks in Pancreatic Cancer Subtype SwitchCumulative thesis
Date of Examination:2023-10-12
Date of issue:2023-10-19
Advisor:Dr. Shiv K. Singh
Referee:Dr. Shiv K. Singh
Referee:Prof. Dr. Argyris Papantonis
Referee:Prof. Dr. Dr. Patrick C. Hermann
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EnglishPancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous disease characterized by a dismal prognosis of 11%, projected to be the second-leading cause of cancer-related death by 2040. This urgent clinical challenge has been attributed in part to high molecular plasticity. In the last decade, two main prognostically relevant transcriptomic subtypes have been defined, namely the classical (CLA) subtype with well-differentiated tumors and good prognosis, and the basal-like (BL), conferring a highly invasive, poorly differentiated, and therapy-resistant identity, translating into poor patient outcome. Further, certain extrinsic microenvironmental (or therapy-induced) cues can shape subtype heterogeneity, leading to dynamic neoplastic-epithelial and stromal-immune interactions. Here, using patient sequencing and bioimaging data, combined with patient-derived, pre-clinical and in vitro models, we show that the cytokine TNF-α, secreted by tumor-associated macrophages in the tumor microenvironment, promotes BL neoplastic subtype identity in PDAC. Using RNA-, ChIP-, ATAC-, and i4C-seq, we uncovered that intrinsically, TNF-α induces cJUN/AP1 signaling, relayed by long-range enhancer-dependent induction of cJUN by BRD4, to promote inflammatory signaling via secretion of macrophage recruiter CCL2, thus inducing BL aggressiveness. Contrastingly, the CLA subtype, which expresses the analogous JUNB/AP1 transcription factor, represses the TNF-α-dependent pro-BL inflammatory signatures (including cJUN) via HDAC1-mediated epigenetic regulation, leading to improved clinical outcome. Importantly, cJUN/AP1+ tumor cells can shape this AP1 dichotomy via recruitment of TNF-α+ macrophages, thereby indirectly repressing JUNB functions. The suppression of JUNB by TNF-α is linked to a pro-inflammatory response associated with exclusion of cytotoxic T cells. Together, we identified two promising treatment approaches for cJUN/AP1high BL PDAC that have demonstrated prolonged survival in preclinical murine models. First, inhibition of BRD4 by JQ1 effectively halts cJUN/AP1-dependent pro-BL signaling and TNF-α+ macrophage recruitment. Second, combined inhibition of TNF-α with chemotherapy decreases TNF-α+ macrophage infiltration and restores cytotoxic CD3+/CD8+ T cells. Hence, targeting intrinsic AP1 dichotomy or extrinsic signals may disrupt subtype heterogeneity and tumor immune cross-talk, thus improving clinical outcome.
Keywords: pancreatic cancer; epigenetics; JUN/AP1; tumor microenvironment; subtype switch; macrophages; spatial heterogeneity
Schlagwörter: pancreatic cancer; epigenetics; JUN/AP1; tumor microenvironment; subtype switch; macrophages; spatial heterogeneity