Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
Project description:We examined the intratumor heterogeneity in S2-VP10 xenograft by single-cell RNA-sequencing. We found a hierarchical tumor progression originating from ROR1high cells with a partial EMT gene signature. We also found that ROR1high cells have the strong capacity as tumor-initiating cells to support tumorigenecity, chemoresistance, and metastasis. CUT&RUN and ATAC-sequencing revealed that ROR1 gene expression is regulated through YAP-BRD4 axis. Together, these data uncover a role for ROR1high cells in tumor progression, suggesting that ablating ROR1high tumor-initiating cells may be the alternative therapeutic strategy in pancreatic adenocarcinoma.
Project description:Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here, we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNAs drive varying levels of MYC dosage, depending on their regulatory landscape, enabling cancer cells to rapidly and reversibly adapt to microenvironmental changes. In absence of selective pressure, a high ecDNA copy number imposes a substantial fitness cost on PDAC cells. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors. Our work provides the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.
Project description:Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here, we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNAs drive varying levels of MYC dosage, depending on their regulatory landscape, enabling cancer cells to rapidly and reversibly adapt to microenvironmental changes. In absence of selective pressure, a high ecDNA copy number imposes a substantial fitness cost on PDAC cells. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors. Our work provides the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.