Research I
A summary of the Petriz lab research interests


Summary of our Research:
The ability to bridge large-scale and single-cell approaches at a functional level are key to identify biomarkers expressed on rare cells. We translate biomedical science into integrated clinical practice and public health by using certified transference processes in cooperation with trusted allies and partners supporting biomedical research. More specifically, we are interested in investigating and developing experimental approaches key to understand the principles underlying the emergence and prevention of cancer therapy resistance.

Description of our Research:

Our lab utilizes cutting-edge cellular-based research tools on a new view of the characterization of cells and subcellular compartments, involving the use of fluorescent tracers coupled with measurements for detecting antigens or markers, a particular nucleic acid sequence, enzymatic activities, the regulation of protein function through conformational modulation, or the role of multidrug resistance transporters as epigenetic interplayers. Functional cytomics enables discovery and characterization of novel cell subsets, mechanisms of resistance to immunotherapy and chemotherapy, and multiplexed measurements of cells for detecting the presence or absence of malignant clones at a single-cell level. We are mainly focused on the cellular and molecular mechanisms controlling the proliferation and differentiation of leukemic stem cells. We are particularly interested in how these mechanisms operate at different disease refractory processes within hematological malignancies.

colonias

Since more than three decades, we study the implications of multidrug resistance transporters in stem cell biology. The cancer stem cell (CSC) model has been established as a cellular mechanism that contributes to phenotypic and functional heterogeneity in diverse cancer types. Recent observations, however, have highlighted many complexities and challenges: the CSC phenotype can vary substantially between patients, tumours may harbour multiple phenotypically or genetically distinct CSCs, metastatic CSCs can evolve from primary CSCs, and tumour cells may undergo reversible phenotypic changes. Although the CSC concept will have clinical relevance in specific cases, accumulating evidence suggests that it will be imperative to target all CSC subsets within the tumour to prevent relapse. In cancer therapy, detailed understanding of the effects of drugs on signal transduction pathways in the target cells is of pivotal relevance in tailoring individualized therapeutic approaches. Furthermore, new and more detailed diagnostics will help to specifically design a therapy for the individual patient.

The group focuses on interdisciplinary projects that cover basic biology through to practical biomedical applications through the measurement of human cancer cells. Our ongoing research projects cover innovative approaches to study the expression of primitive stem cell markers during origin, progression, maintenance of cancer and its management; the quality and safety assessment of hematopoietic blood progenitor and stem cell grafts; the role of myeloid derived suppressor cells in immunotherapy and targeted therapy for clinical decision-making; new cytomic strategies for whole blood and marrow immunostaining; the use of natural compounds for cancer treatment; and the accurate detection and significance of minimal residual disease in acute leukemia. We are currently evaluating evidence of mechanisms by which ABC transporters differentially activates low- or high-level transduction cell signaling and their potential role as epigenetic interplayers to protect and mitigate the stem cell compartment from therapeutic damage.

Research is now well underway to develop sophisticated methods for identifying patient populations who will most likely respond to specific interventions. While we have made significant strides in cancer research over the past two decades, there is plenty of work left to do and make “visible the invisible”. Cancer stem cells are rare and elusive cells and our research is critical for developing new experimental strategies to evaluate the cellular response to anticancer therapies. We are committed to accelerate the application of new sophisticated cytomic strategies and, importantly, uniquely placed to improve prevention, diagnosis, prognosis, therapy, and the health of patients of all ages.

WI SIC 2016

Main scientific, technical or innovation applications of our work

Following sample preparation, a cytomic assay is typically straightforward, less time-consuming, less labour-intensive than other cellular multiplexing assays, and aimed at to determine the molecular phenotype of single-cells. New methods to identify, characterize, isolate, expand, target and track CSCs and test their relevance in clinical prognostic and treatment settings offer the possibility of major advances in cancer prevention and treatment. Progress is currently limited by lack of: coordinated, consensus methods, consistent mechanisms to accrue and access patient samples, and the ability to apply investigative methods and share material and data on a large scale.

Main scientific, technical or innovation applications of our work will help to:

• Provide access to new and expanded resource and technology platforms essential to accelerate breakthroughs in cancer prevention, diagnosis and treatment that develop or exploit new knowledge about CSC populations.
• Enable storage and sharing of biological samples and data using defined methods that meet common standards and are readily transportable.
• Facilitate exchange and cross-training of investigators and support staff engaged in CSC research at all levels and across disciplines.
• Promote the development of new technologies that support the discovery and translation of CSC-relevant research as a critical step in changing the prevention and management of cancer.
• Help laboratory personnel to identify, acquire, and implement the appropriate software to analyze adequately the growing number of complex datasets in flow cytometry.


Main scientific, technical or innovation applications of our work will help to:

Following sample preparation, a cytomic assay is typically straightforward, less time-consuming, less labour-intensive than other cellular multiplexing assays, and aimed at to determine the molecular phenotype of single-cells. New methods to identify, characterize, isolate, expand, target and track CSCs and test their relevance in clinical prognostic and treatment settings offer the possibility of major advances in cancer prevention and treatment. Progress is currently limited by lack of: coordinated, consensus methods, consistent mechanisms to accrue and access patient samples, and the ability to apply investigative methods and share material and data on a large scale.

• Provide access to new and expanded resource and technology platforms essential to accelerate breakthroughs in cancer prevention, diagnosis and treatment that develop or exploit new knowledge about CSC populations.

• Enable storage and sharing of biological samples and data using defined methods that meet common standards and are readily transportable.

• Facilitate exchange and cross-training of investigators and support staff engaged in CSC research at all levels and across disciplines.

• Promote the development of new technologies that support the discovery and translation of CSC-relevant research as a critical step in changing the prevention and management of cancer.

• Help laboratory personnel to identify, acquire, and implement the appropriate software to analyze adequately the growing number of complex datasets in flow cytometry.

1536 wells

Main social impact features of our work

The patient’s condition can change dramatically in a short period of time due to treatment and illness. Complications developed by these patients are known to have better outcomes with earlier identification and management, and collaboration between different supporting disciplines is of great importance. Given that current clinical application of functional cytomics remains largely confined to few specific academic centers, our goal is to provide the patients with a wide range of scientific support strategies, through precision, oversight and accuracy to integrate:

• Clinical implementation of functional cytomic asays. Precision/personalized high-quality assays for individual patients, by integrating functional cytomics to accelerate new experimental approaches for ex vivo and in vivo drug sensitivity.

• Translation of functional screening into novel clinical strategies. Measure the impact of exogenous interventions such as drug exposure on tumor cell phenotype. Functional screening deliver precise cytome information regarding the capacity of drugs to elicit apoptotic responses/drug resistance of cancer cells without a prior knowledge of the molecular mechanistic underpinnings of such responses.

• The understanding of drug resistance and the prediction of effective drug combinations. Examples include strategies to tackle resistance to tyrosine kinase inhibitors in a rare population of cancer stem cells named the "side population" from patients with chronic myelogenous leukemia, myelodisplastic syndromes, acute leukemia, and other malignant hematologic diseases that affect patients of all ages.

• The reduction of costs by obtaining specialized instrumentation and personnel for execution of cytomic screens in partnership with stakeholders and biotechnological partners.

• Functional and immunophenotyping data sets aimed at understanding complex functional-to-phenotype correlations and, thereby, accelerate discovery of the biology of leukemogenesis as well as the clinical implementation of novel therapies.
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Three questions we are trying to answer with our research:

• What defines a stem cell in functional and phenotypic terms?
• How can we both evaluate and reverse drug/immunotherapy resistance?
• Why should we care about the oxygen in the metabolic/tumour microenvironment?



What do we think are the most important social impact results of our work?
Cancer is a complex group of diseases with serious implications not just for individuals and their families, but also for society in general and health a system in particular, remains an important health challenge. Patients can respond differently to the same medicine, and many patients do not benefit from the first drug they are offered in treatment. Because personalized medicine is able to provide the right therapy, in the right dose, improving patient stratification and prediction of disease, we expect to make available:

• Better diagnosis and earlier intervention. Cytome analysis could determine precisely whether patients are susceptible to drug toxicities, and choose the optimal treatment strategy.

• Individualized drug selection. Here we consider which molecular and functional models best predict how a patient will respond to a therapy to develop accurate and cost-effective tests. Clinicians will have fundamental information for decision-making and select the optimal care. In addition, functional testing could help to select the best drug usage and schedule or combination, when indicated, with anticancer natural products.

• Drug development challenges. A better understanding of clinical observations made during individualized drug development and conventional therapy will help to identify new disease subtypes and their associated molecular pathways, and design drugs that target them with more efficient trials. Cytome analysis could also help to select patients for inclusion in, or exclusion from, and assay new drugs medicines that might otherwise be abandoned considered being ineffective in non-individualized patient populations.


Keywords

Cytometry, stem cells, cancer stem cells, fluorescence, toxicology, pharmacology, immunotherapy, cytome, phenotype, drug discovery, high-content analysis, data mining, high-throughput screening, bioinformatics, human cytome project.