Adaptive drug-resistance mechanisms allow human tumors to evade treatment through selection and expansion of treatment-resistant clones. Modeling the functional heterogeneity of tumors can unmask critical contributions of distinct tumor cell sub-populations toward identifying rational drug combinations. Here, studying clonal evolution of tumor cells derived from human pancreatic tumors, we demonstrate that in vitro adherent cultures and in vivo tumors are maintained by a common set of long term self-renewing tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of clonal dynamics and adaptive responses to therapeutic challenge over time, we uncovered that the tumorigenic compartment of pancreatic tumors maintains a multitude of functionally heterogeneous subpopulations of cells with differential degrees of sensitivity to therapeutics. High-throughput isolation and deep characterization of unique clonal lineages showed genetic and transcriptomic diversity underlying the functionally diverse subpopulations, positioning the origins of tumor heterogeneity within the long-term self-renewing compartment. Molecular annotation of gemcitabine-naïve clonal lineages with distinct responses to treatment in the context of CRTs generated signatures that can predict the response to chemotherapy and exposed pre-existing functional mechanisms of clonal resistance, primarily associated to DNA damage tolerance and mitochondrial respiration (OXPHOS). Further transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation showed that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate OXPHOS. Combining a novel inhibitor of oxidative phosphorylation (IACS-10759) developed at the MD Anderson Institute for Applied Cancer Science, and currently in phase I clinical trial in acute myeloid leukemia and solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation. Our study, correlating genomic and transcriptomic traits with specific functional phenotypes, uncovered new mechanisms that underlie intra-tumor sub-clonal heterogeneity, influence treatment response to drugs and sustain tumor relapse.

Dissection of clonal heterogeneity unmasks pre-existing chemoresistance and new metabolic vulnerabilities in pancreatic cancer

Sapio, Luigi;
2019

Abstract

Adaptive drug-resistance mechanisms allow human tumors to evade treatment through selection and expansion of treatment-resistant clones. Modeling the functional heterogeneity of tumors can unmask critical contributions of distinct tumor cell sub-populations toward identifying rational drug combinations. Here, studying clonal evolution of tumor cells derived from human pancreatic tumors, we demonstrate that in vitro adherent cultures and in vivo tumors are maintained by a common set of long term self-renewing tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of clonal dynamics and adaptive responses to therapeutic challenge over time, we uncovered that the tumorigenic compartment of pancreatic tumors maintains a multitude of functionally heterogeneous subpopulations of cells with differential degrees of sensitivity to therapeutics. High-throughput isolation and deep characterization of unique clonal lineages showed genetic and transcriptomic diversity underlying the functionally diverse subpopulations, positioning the origins of tumor heterogeneity within the long-term self-renewing compartment. Molecular annotation of gemcitabine-naïve clonal lineages with distinct responses to treatment in the context of CRTs generated signatures that can predict the response to chemotherapy and exposed pre-existing functional mechanisms of clonal resistance, primarily associated to DNA damage tolerance and mitochondrial respiration (OXPHOS). Further transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation showed that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate OXPHOS. Combining a novel inhibitor of oxidative phosphorylation (IACS-10759) developed at the MD Anderson Institute for Applied Cancer Science, and currently in phase I clinical trial in acute myeloid leukemia and solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation. Our study, correlating genomic and transcriptomic traits with specific functional phenotypes, uncovered new mechanisms that underlie intra-tumor sub-clonal heterogeneity, influence treatment response to drugs and sustain tumor relapse.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11591/463475
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