Minimal residual disease in cancer therapy – Small things make all the difference

Blatter, Sohvi; Rottenberg, Sven

doi:10.1016/j.drup.2015.08.003

Cited by 39 publications

(31 citation statements)

References 93 publications

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“…It is unclear whether either dormancy or drug resistance is pivotal in respect to the other, so that dormancy is a consequence of resistance or vice versa (Blatter and Rottenberg, 2015). Our two complementary mouse models show that LRC were defined by their dormant nature and displayed drug resistance, while MRD cells were defined by their ability to survive drug treatment and displayed a dormant phenotype.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

et al. 2016

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SummaryTumor relapse is associated with dismal prognosis, but responsible biological principles remain incompletely understood. To isolate and characterize relapse-inducing cells, we used genetic engineering and proliferation-sensitive dyes in patient-derived xenografts of acute lymphoblastic leukemia (ALL). We identified a rare subpopulation that resembled relapse-inducing cells with combined properties of long-term dormancy, treatment resistance, and stemness. Single-cell and bulk expression profiling revealed their similarity to primary ALL cells isolated from pediatric and adult patients at minimal residual disease (MRD). Therapeutically adverse characteristics were reversible, as resistant, dormant cells became sensitive to treatment and started proliferating when dissociated from the in vivo environment. Our data suggest that ALL patients might profit from therapeutic strategies that release MRD cells from the niche.

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Section: Discussionmentioning

confidence: 99%

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

et al. 2016

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“…It is not clear whether these TNFα-responsive clones exist within the primary tumor population, perhaps as recurrence-competent stem cells (31), or whether this RCP is acquired by ongoing mutation during the response to first-line therapy (9, 14, 29, 30). As established primary B16 and B16 MRD tumors both have low intratumoral NK infiltration, we hypothesize that the differential recognition of B16 or B16 MRD cells by NK cells occurs at very early stages of tumor development.…”

Section: Discussionmentioning

confidence: 99%

“…Dormancy is characterized by presence of residual tumor cells [minimal residual disease (MRD); ref. 14] and can last for decades (2, 5, 15–17). …”

Section: Introductionmentioning

confidence: 99%

Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence

Kottke

Evgin

Shim

et al. 2017

Cancer Immunology Research

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Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment-resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immunosurveillance. In the first, the role of TNFα changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)–mediated cytokine response characterized by low IL6 and elevated IFNγ, PD-L1hi MRD cells promoted the secretion of IL6 but minimal IFNγ, inhibiting both NK-cell and T-cell surveillance. Tumor recurrence was promoted by trauma- or infection-like stimuli inducing VEGF and TNFα, which stimulated the growth of MRD tumors. Finally, therapies that blocked PD-1, TNFα, or NK cells delayed or prevented recurrence. These data show how innate immunosurveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identify therapeutic targets in patients with MRD known to be at high risk of relapse.

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“…In all three cases our data revealed subpopulations of cells with slow OCR and ECAR in both control and treated cells. While further studies are necessary to reveal the functional role of these cells at the population and tissue level, it is possible that due to their dormant-like metabolic phenotype behavior these cells may play a role in drug response and cancer recurrence after treatment3132.…”

Section: Discussionmentioning

confidence: 99%

A platform for high-throughput bioenergy production phenotype characterization in single cells

Kelbauskas

Glenn

Anderson

et al. 2017

Sci Rep

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Driven by an increasing number of studies demonstrating its relevance to a broad variety of disease states, the bioenergy production phenotype has been widely characterized at the bulk sample level. Its cell-to-cell variability, a key player associated with cancer cell survival and recurrence, however, remains poorly understood due to ensemble averaging of the current approaches. We present a technology platform for performing oxygen consumption and extracellular acidification measurements of several hundreds to 1,000 individual cells per assay, while offering simultaneous analysis of cellular communication effects on the energy production phenotype. The platform comprises two major components: a tandem optical sensor for combined oxygen and pH detection, and a microwell device for isolation and analysis of single and few cells in hermetically sealed sub-nanoliter chambers. Our approach revealed subpopulations of cells with aberrant energy production profiles and enables determination of cellular response variability to electron transfer chain inhibitors and ion uncouplers.

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Minimal residual disease in cancer therapy – Small things make all the difference

Cited by 39 publications

References 93 publications

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence

A platform for high-throughput bioenergy production phenotype characterization in single cells

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