Sex: Female
Education:
- Doctor of Philosophy in Medical Science, Kyoto University Japan, 2015
- Master of Science in Biochemistry, University of the Philippines, 2010
- Bachelor of Science in Biology/Biological Sciences, University of the Philippines, 2001
Field of Specialization
Cell culture
Cell Signaling
Flow Cytometry
Western Blot Analysis
Immunohistochemistry
Immunofluorescence
Gene Expression
Cell Line Culture
Cancer Biology
Molecular Cell Biology
Researches:
Article title: Cycling cancer persister cells arise from lineages with distinct programs
Authors: Yaara Oren, Michael Tsabar, Michael S. Cuoco1, Liat Amir-Zilberstein, Heidie F. Cabanos, et al.
Publication title: Nature 596(7873):1-7, August 2021
Abstract:
Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell’s clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence. Lineage tracing by barcoding of individual cells using a lentivirus library shows that cycling and non-cycling drug-tolerant persister cells in cancer arise from different lineages with distinct transcriptional and metabolic programs.
Full text link https://tinyurl.com/r6xucpj6
Article title: Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer
Authors: Kamrine E. Poels, Adam J. Schoenfeld, Alex Makhnin, Yosef Tobi, Yuli Wang, et al.
Publication title: Nature Communications 12(1):3697, June 2021
Abstract:
Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting. Osimertinib and dacomitinib are approved as first-line treatment of EGFR-mutant NSCLC but resistance can arise. Here, the authors use a computational model to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy that was confirmed tolerable and effective in an ongoing phase I clinical trial.
Full text link https://tinyurl.com/2xtdtt27
Article title: APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer
Authors: Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su, et al.
Publication title: *Preprint
Abstract:
Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.
Full text link https://tinyurl.com/53kxwx5r
Article title: Cycling cancer persister cells arise from lineages with distinct transcriptional and metabolic programs
Authors: Yaara Oren, Michael Tsabar, Heidie F. Cabanos, Michael S. Cuoco, Elma Zaganjor, et al.
Publication title: *Preprint
Abstract:
Non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer (Salgia and Kulkarni, 2018), where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment (Vallette et al., 2019). While most cancer persisters, like their bacterial counterparts, remain arrested in the presence of drug, a rare subset of cancer persisters can re-enter the cell cycle under constitutive drug treatment (Sharma et al., 2010). Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drug. Here, using time-lapse imaging, we found that cycling persisters emerge early in the course of treatment of EGFR-mutant lung cancer cells with the EGFR inhibitor osimertinib. To study this rare, transiently-resistant, proliferative persister population we developed Watermelon, a new high-complexity expressed barcode lentiviral library for simultaneous tracing each cell’s clonal origin, proliferative state, and transcriptional state. Analysis of Watermelon-transduced PC9 cells demonstrated that cycling and non-cycling persisters arise from different pre-existing cell lineages with distinct transcriptional and metabolic programs. The proliferative capacity of persisters is associated with an upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation in specific subpopulations of tumor cells. Mitigating oxidative stress or blocking metabolic reprograming significantly alters the fraction of cycling persister cells. In human tumors, programs associated with cycling persisters were induced in malignant cells in response to multiple tyrosine kinase inhibitors. The Watermelon system enabled the identification of rare persister lineages, that are preferentially poised through specific gene programs to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.
Full text link https://tinyurl.com/3zj5vc8d
Article title: Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
Authors: Sana Raoof, Iain J. Mulford, Heidie Frisco-Cabanos, Varuna Nangia, Daria Timonina, et al.
Publication title: Oncogene 38(37):1, September 2019
Abstract:
Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug-tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFRT790M mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified fibroblast growth factor receptor 1 (FGFR1) as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data have not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug-tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for the clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.
Full text link https://tinyurl.com/hh6p5muk
Article title: Synthetic Molecules that Protect Cells from Anoikis and Their Use in Cell Transplantation
Authors: Heidie L. Frisco-Cabanos, Dr. Mizuki Watanabe, Dr. Naoki Okumura, Dr. Kosuke Kusamori, Naohiro Takemoto, et al.
Publication title: Angewandte Chemie 126(42), October 2014
Abstract:
One of the major problems encountered in cell transplantation is the low level of survival of transplanted cells due to detachment-induced apoptosis, called anoikis. The present study reports on the chemical synthesis and biological evaluation of water-soluble molecules that protect suspended cells from anoikis. The synthetic molecules bind to and induce clusters of integrins and heparan-sulfate-bound syndecans, two classes of receptors that are important for extracellular matrix-mediated cell survival. Molecular biological analysis indicates that such molecules prolong the survival of suspended NIH3T3 cells, at least in part, by promoting clustering of syndecan-4 and integrin β1 on the cell surface, leading to the activation of small GTPase Rac-1 and Akt. In vivo experiments using animal disease models demonstrated the ability of the molecules to improve cell engraftment. The cluster-inducing molecules may provide a starting point for the design of new synthetic tools for cell-based therapy.
Full text available upon request to the author
Papers Presented:
Article title: Targeting the root of cancer persister cells using an expressed barcode library
Authors: Yaara Oren, Pratiksha Thakore, Mike S. Cuoco, Heidie Frisco Cabanos, Aaron Hata, et al.
Conference title: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA
Abstract:
Despite a favorable initial response, many cancer patients will experience recurrence of disease within months or years after diagnosis. Recurrence largely arises as a result of the growth of residual cancer cells that remain after treatment. The ability of a subset of cells to survive is attributed frequently to genetic heterogeneity, however recently it was shown that in multiple cancer types relapse can arise due to the presence of persister cells. Persisters are a subpopulation of transiently drug-tolerant cells that are able to survive therapy through reversible, non-mutational mechanisms. Tumor dormancy, stochastic cell state shifts and stem cell-like populations are amongst the mechanisms hypothesized to underlie persister phenotype. However, given the lack of high-throughput methods to concurrently track cell state and lineage, it is not currently feasible to distinguish the relative contribution of each of these factors. To address this need, we generated the Watermelon library. The Watermelon library is a high-complexity expressed barcode library that enables simultaneous tracing of lineage as well as the transcriptional and proliferative state of each cell in the population during drug treatment. We have applied the watermelon system to study the mechanisms underlying the ability of a small population of cells to regain proliferative capacity under constant treatment with EGFR tyrosine kinase inhibitors. We combine time-lapse imaging with single-cell RNA sequencing to show that early drug-cyclers do not acquire a facilitating resistance mutation but rather transition to a new cell state. We find that this non-genetic drug-proliferative state is not restricted to a certain clonal lineage and can be reached by distinct transcriptional paths. We anticipate that this unique library, which can be applied to other systems, would facilitate a better understanding of the cellular and molecular pathways that affect non-inherited drug resistance. Citation Format: Yaara Oren, Pratiksha Thakore, Mike S. Cuoco, Heidie Frisco Cabanos, Aaron Hata, Joan S. Brugge, Aviv Regev. Targeting the root of cancer persister cells using an expressed barcode library
Full text available upon request to the author