Abstract:Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Here, by employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cel… Show more
“…Elegant studies discovered that BET family member bromodomain containing 4 (BRD4) maintained cJUN expression which resulted in the recruitment of TNF-alpha positive macrophages via the BRD4-cJUN/AP1-CCL2 axis and subsequent TNF-alpha-mediated classical-to-basal subtype switch [ 60 ]. In addition, cJUN collaborates with progenitor transcription factors, like Sox2, Sox5, Prrx1, Twist2, or Nr2f2 to overcome Yap dependency [ 61 ], which is associated with an EMT state that is different from classical TGF-beta-driven EMT. YAP-independent PDAC can be targeted with BETi, and therefore, the combination of BETi with YAPi exhibits synergism [ 61 ].…”
Section: Histone Modifiers In Pdac Metastasismentioning
confidence: 99%
“…In addition, cJUN collaborates with progenitor transcription factors, like Sox2, Sox5, Prrx1, Twist2, or Nr2f2 to overcome Yap dependency [ 61 ], which is associated with an EMT state that is different from classical TGF-beta-driven EMT. YAP-independent PDAC can be targeted with BETi, and therefore, the combination of BETi with YAPi exhibits synergism [ 61 ]. Fig.…”
Section: Histone Modifiers In Pdac Metastasismentioning
Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.
“…Elegant studies discovered that BET family member bromodomain containing 4 (BRD4) maintained cJUN expression which resulted in the recruitment of TNF-alpha positive macrophages via the BRD4-cJUN/AP1-CCL2 axis and subsequent TNF-alpha-mediated classical-to-basal subtype switch [ 60 ]. In addition, cJUN collaborates with progenitor transcription factors, like Sox2, Sox5, Prrx1, Twist2, or Nr2f2 to overcome Yap dependency [ 61 ], which is associated with an EMT state that is different from classical TGF-beta-driven EMT. YAP-independent PDAC can be targeted with BETi, and therefore, the combination of BETi with YAPi exhibits synergism [ 61 ].…”
Section: Histone Modifiers In Pdac Metastasismentioning
confidence: 99%
“…In addition, cJUN collaborates with progenitor transcription factors, like Sox2, Sox5, Prrx1, Twist2, or Nr2f2 to overcome Yap dependency [ 61 ], which is associated with an EMT state that is different from classical TGF-beta-driven EMT. YAP-independent PDAC can be targeted with BETi, and therefore, the combination of BETi with YAPi exhibits synergism [ 61 ]. Fig.…”
Section: Histone Modifiers In Pdac Metastasismentioning
Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.
Phenotypic plasticity, the capacity of cells to transition between distinct phenotypic and lineage states over time, is a genetically and epigenetically encoded trait essential for normal development and adult tissue homeostasis. In cancer, phenotypic plasticity programs can be deployed aberrantly to enable disease progression and acquired therapeutic resistance. Cancer phenotypic plasticity is a current barrier to achieving cures for advanced cancers using available molecularly targeted therapies. This review summarizes the complex and interconnected molecular pathways implicated in phenotypic plasticity, both in the context of normal tissue homeostasis and cancer. Molecular pathways convergent between these contexts are highlighted while pathways enabling plasticity are distinguished from those that specify the phenotype of already plastic cells. Key unresolved questions in the field are discussed along with emerging technologies that may be used to help answer them.
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