The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

Cassidy, Tyler; Nichol, Daniel; Robertson-Tessi, Mark; Craig, Morgan; Anderson, Alexander R. A.; Wodarz, ed., Dominik

doi:10.1371/journal.pcbi.1009348

The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

Journal Article · Mon Aug 30 00:00:00 EDT 2021 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1009348· OSTI ID:1819478

; ; ; ; ; Wodarz, ed., Dominik

Intra-tumour heterogeneity is a leading cause of treatment failure and disease progression in cancer. While genetic mutations have long been accepted as a primary mechanism of generating this heterogeneity, the role of phenotypic plasticity is becoming increasingly apparent as a driver of intra-tumour heterogeneity. Consequently, understanding the role of this plasticity in treatment resistance and failure is a key component of improving cancer therapy. We develop a mathematical model of stochastic phenotype switching that tracks the evolution of drug-sensitive and drug-tolerant subpopulations to clarify the role of phenotype switching on population growth rates and tumour persistence. By including cytotoxic therapy in the model, we show that, depending on the strategy of the drug-tolerant subpopulation, stochastic phenotype switching can lead to either transient or permanent drug resistance. We study the role of phenotypic heterogeneity in a drug-resistant, genetically homogeneous population of non-small cell lung cancer cells to derive a rational treatment schedule that drives population extinction and avoids competitive release of the drug-tolerant sub-population. This model-informed therapeutic schedule results in increased treatment efficacy when compared against periodic therapy, and, most importantly, sustained tumour decay without the development of resistance.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1819478

Journal Information:: PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 8 Vol. 17; ISSN 1553-7358

Publisher:: Public Library of Science (PLoS)Copyright Statement

Country of Publication:: United States

Language:: English

References (66)

On the definition and the computation of the basic reproduction ratio R 0 in models for infectious diseases in heterogeneous populations Diekmann, O.; Heesterbeek, J. A. P.; Metz, J. A. J. Journal of Mathematical Biology, Vol. 28, Issue 4 https://doi.org/10.1007/BF00178324	journal	June 1990
On a new perspective of the basic reproduction number in heterogeneous environments Inaba, Hisashi Journal of Mathematical Biology, Vol. 65, Issue 2 https://doi.org/10.1007/s00285-011-0463-z	journal	August 2011
Mass concentration in a nonlocal model of clonal selection Busse, J. -E.; Gwiazda, P.; Marciniak-Czochra, A. Journal of Mathematical Biology, Vol. 73, Issue 4 https://doi.org/10.1007/s00285-016-0979-3	journal	March 2016
Adaptation to Stochastic Temporal Variations in Intratumoral Blood Flow: The Warburg Effect as a Bet Hedging Strategy Gravenmier, Curtis A.; Siddique, Miriam; Gatenby, Robert A. Bulletin of Mathematical Biology, Vol. 80, Issue 5 https://doi.org/10.1007/s11538-017-0261-x	journal	May 2017
Micropharmacology: An In Silico Approach for Assessing Drug Efficacy Within a Tumor Tissue Karolak, Aleksandra; Rejniak, Katarzyna A. Bulletin of Mathematical Biology, Vol. 81, Issue 9 https://doi.org/10.1007/s11538-018-0402-x	journal	February 2018
Characterizing Chemotherapy-Induced Neutropenia and Monocytopenia Through Mathematical Modelling Cassidy, Tyler; Humphries, Antony R.; Craig, Morgan Bulletin of Mathematical Biology, Vol. 82, Issue 8 https://doi.org/10.1007/s11538-020-00777-0	journal	July 2020
Persister cells and tolerance to antimicrobials Keren, Iris; Kaldalu, Niilo; Spoering, Amy FEMS Microbiology Letters, Vol. 230, Issue 1 https://doi.org/10.1016/S0378-1097(03)00856-5	journal	January 2004
Cell population heterogeneity and evolution towards drug resistance in cancer: Biological and mathematical assessment, theoretical treatment optimisation Chisholm, Rebecca H.; Lorenzi, Tommaso; Clairambault, Jean Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1860, Issue 11 https://doi.org/10.1016/j.bbagen.2016.06.009	journal	November 2016
Tumor heterogeneity: Causes and consequences Marusyk, Andriy; Polyak, Kornelia Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Vol. 1805, Issue 1 https://doi.org/10.1016/j.bbcan.2009.11.002	journal	January 2010
A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations Sharma, Sreenath V.; Lee, Diana Y.; Li, Bihua Cell, Vol. 141, Issue 1 https://doi.org/10.1016/j.cell.2010.02.027	journal	April 2010
Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells Gupta, Piyush B.; Fillmore, Christine M.; Jiang, Guozhi Cell, Vol. 146, Issue 4 https://doi.org/10.1016/j.cell.2011.07.026	journal	August 2011
Memory Sequencing Reveals Heritable Single-Cell Gene Expression Programs Associated with Distinct Cellular Behaviors Shaffer, Sydney M.; Emert, Benjamin L.; Reyes Hueros, Raúl A. Cell, Vol. 182, Issue 4 https://doi.org/10.1016/j.cell.2020.07.003	journal	August 2020
Endogenous Replication Stress in Mother Cells Leads to Quiescence of Daughter Cells Arora, Mansi; Moser, Justin; Phadke, Harsha Cell Reports, Vol. 19, Issue 7 https://doi.org/10.1016/j.celrep.2017.04.055	journal	May 2017
Prolonged Prometaphase Blocks Daughter Cell Proliferation Despite Normal Completion of Mitosis Uetake, Yumi; Sluder, Greenfield Current Biology, Vol. 20, Issue 18 https://doi.org/10.1016/j.cub.2010.08.018	journal	September 2010
Bet-hedging in stochastically switching environments Müller, J.; Hense, B. A.; Fuchs, T. M. Journal of Theoretical Biology, Vol. 336 https://doi.org/10.1016/j.jtbi.2013.07.017	journal	November 2013
Understanding the role of phenotypic switching in cancer drug resistance Gunnarsson, Einar Bjarki; De, Subhajyoti; Leder, Kevin Journal of Theoretical Biology, Vol. 490 https://doi.org/10.1016/j.jtbi.2020.110162	journal	April 2020
Toward understanding of the role of reversibility of phenotypic switching in the evolution of resistance to therapy Horvath, D.; Brutovsky, B. Physics Letters A, Vol. 382, Issue 24 https://doi.org/10.1016/j.physleta.2018.03.052	journal	June 2018
The evolution of bet-hedging adaptations to rare scenarios King, Oliver D.; Masel, Joanna Theoretical Population Biology, Vol. 72, Issue 4 https://doi.org/10.1016/j.tpb.2007.08.006	journal	December 2007
Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me’ Pisco, A. O.; Huang, S. British Journal of Cancer, Vol. 112, Issue 11 https://doi.org/10.1038/bjc.2015.146	journal	May 2015
Dynamics of multiple myeloma tumor therapy with a recombinant measles virus Dingli, D.; Offord, C.; Myers, R. Cancer Gene Therapy, Vol. 16, Issue 12 https://doi.org/10.1038/cgt.2009.40	journal	June 2009
Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance Shaffer, Sydney M.; Dunagin, Margaret C.; Torborg, Stefan R. Nature, Vol. 546, Issue 7658 https://doi.org/10.1038/nature22794	journal	June 2017
Competing memories of mitogen and p53 signalling control cell-cycle entry Yang, Hee Won; Chung, Mingyu; Kudo, Takamasa Nature, Vol. 549, Issue 7672 https://doi.org/10.1038/nature23880	journal	September 2017
Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells Ramirez, Michael; Rajaram, Satwik; Steininger, Robert J. Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms10690	journal	February 2016
Non-Darwinian dynamics in therapy-induced cancer drug resistance Pisco, Angela Oliveira; Brock, Amy; Zhou, Joseph Nature Communications, Vol. 4, Issue 1 https://doi.org/10.1038/ncomms3467	journal	September 2013
Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition Goldman, Aaron; Majumder, Biswanath; Dhawan, Andrew Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms7139	journal	February 2015
Understanding and targeting resistance mechanisms in NSCLC Rotow, Julia; Bivona, Trever G. Nature Reviews Cancer, Vol. 17, Issue 11 https://doi.org/10.1038/nrc.2017.84	journal	October 2017
Cancer drug resistance: an evolving paradigm Holohan, Caitriona; Van Schaeybroeck, Sandra; Longley, Daniel B. Nature Reviews Cancer, Vol. 13, Issue 10 https://doi.org/10.1038/nrc3599	journal	September 2013
Turning ecology and evolution against cancer Korolev, Kirill S.; Xavier, Joao B.; Gore, Jeff Nature Reviews Cancer, Vol. 14, Issue 5 https://doi.org/10.1038/nrc3712	journal	April 2014
The mathematics of cancer: integrating quantitative models Altrock, Philipp M.; Liu, Lin L.; Michor, Franziska Nature Reviews Cancer, Vol. 15, Issue 12 https://doi.org/10.1038/nrc4029	journal	November 2015
Tumour heterogeneity and resistance to cancer therapies Dagogo-Jack, Ibiayi; Shaw, Alice T. Nature Reviews Clinical Oncology, Vol. 15, Issue 2 https://doi.org/10.1038/nrclinonc.2017.166	journal	November 2017
Persister cells, dormancy and infectious disease Lewis, Kim Nature Reviews Microbiology, Vol. 5, Issue 1 https://doi.org/10.1038/nrmicro1557	journal	December 2006
Spatial competition constrains resistance to targeted cancer therapy Bacevic, Katarina; Noble, Robert; Soffar, Ahmed Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-01516-1	journal	December 2017
Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer Zhang, Jingsong; Cunningham, Jessica J.; Brown, Joel S. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-01968-5	journal	November 2017
Age structure landscapes emerge from the equilibrium between aging and rejuvenation in bacterial populations Proenca, Audrey M.; Rang, Camilla Ulla; Buetz, Christen Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06154-9	journal	September 2018
Hidden heterogeneity and circadian-controlled cell fate inferred from single cell lineages Chakrabarti, Shaon; Paek, Andrew L.; Reyes, Jose Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-07788-5	journal	December 2018
Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures Vander Velde, Robert; Yoon, Nara; Marusyk, Viktoriya Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-16212-w	journal	May 2020
Fibroblasts and alectinib switch the evolutionary games played by non-small cell lung cancer Kaznatcheev, Artem; Peacock, Jeffrey; Basanta, David Nature Ecology & Evolution, Vol. 3, Issue 3 https://doi.org/10.1038/s41559-018-0768-z	journal	February 2019
Cooperation among cancer cells: applying game theory to cancer Archetti, Marco; Pienta, Kenneth J. Nature Reviews Cancer, Vol. 19, Issue 2 https://doi.org/10.1038/s41568-018-0083-7	journal	November 2018
Rapid phenotypic individualization of bacterial sister cells Govers, Sander K.; Adam, Antoine; Blockeel, Hendrik Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-08660-0	journal	August 2017
Neighborhood size-effects shape growing population dynamics in evolutionary public goods games Kimmel, Gregory J.; Gerlee, Philip; Brown, Joel S. Communications Biology, Vol. 2, Issue 1 https://doi.org/10.1038/s42003-019-0299-4	journal	February 2019
Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells Dingli, D.; Chalub, F. A. C. C.; Santos, F. C. British Journal of Cancer, Vol. 101, Issue 7 https://doi.org/10.1038/sj.bjc.6605288	journal	September 2009
The Cell Cycle Switch Computes Approximate Majority Cardelli, Luca; Csikász-Nagy, Attila Scientific Reports, Vol. 2, Issue 1 https://doi.org/10.1038/srep00656	journal	September 2012
Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance Su, Yapeng; Wei, Wei; Robert, Lidia Proceedings of the National Academy of Sciences, Vol. 114, Issue 52 https://doi.org/10.1073/pnas.1712064115	journal	December 2017
Evolution of intratumoral phenotypic heterogeneity: the role of trait inheritance Gallaher, Jill; Anderson, Alexander R. A. Interface Focus, Vol. 3, Issue 4 https://doi.org/10.1098/rsfs.2013.0016	journal	August 2013
Model genotype–phenotype mappings and the algorithmic structure of evolution Nichol, Daniel; Robertson-Tessi, Mark; Anderson, Alexander R. A. Journal of The Royal Society Interface, Vol. 16, Issue 160 https://doi.org/10.1098/rsif.2019.0332	journal	November 2019
Genotype–phenotype mapping and the end of the ‘genes as blueprint’ metaphor Pigliucci, Massimo Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 365, Issue 1540 https://doi.org/10.1098/rstb.2009.0241	journal	February 2010
Global microRNA depletion suppresses tumor angiogenesis Chen, S.; Xue, Y.; Wu, X. Genes & Development, Vol. 28, Issue 10 https://doi.org/10.1101/gad.239681.114	journal	May 2014
Density Dependence and Cooperation: Theory and a test with Bacteria Ross-Gillespie, Adin; Gardner, Andy; Buckling, Angus Evolution, Vol. 63, Issue 9 https://doi.org/10.1111/j.1558-5646.2009.00723.x	journal	September 2009
Bacterial Persistence as a Phenotypic Switch Balaban, Nathalie Q.; Merrin, Jack; Chait, Remy Science, Vol. 305, Issue 5690, p. 1622-1625 https://doi.org/10.1126/science.1099390	journal	September 2004
Mechanisms of bacterial persistence during stress and antibiotic exposure Harms, Alexander; Maisonneuve, Etienne; Gerdes, Kenn Science, Vol. 354, Issue 6318 https://doi.org/10.1126/science.aaf4268	journal	December 2016
Temporal integration of mitogen history in mother cells controls proliferation of daughter cells Min, Mingwei; Rong, Yao; Tian, Chengzhe Science, Vol. 368, Issue 6496 https://doi.org/10.1126/science.aay8241	journal	April 2020
Adaptive Therapy Gatenby, Robert A.; Silva, Ariosto S.; Gillies, Robert J. Cancer Research, Vol. 69, Issue 11 https://doi.org/10.1158/0008-5472.CAN-08-3658	journal	June 2009
Impact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes Robertson-Tessi, Mark; Gillies, Robert J.; Gatenby, Robert A. Cancer Research, Vol. 75, Issue 8 https://doi.org/10.1158/0008-5472.CAN-14-1428	journal	April 2015
Emergence of Drug Tolerance in Cancer Cell Populations: An Evolutionary Outcome of Selection, Nongenetic Instability, and Stress-Induced Adaptation Chisholm, Rebecca H.; Lorenzi, Tommaso; Lorz, Alexander Cancer Research, Vol. 75, Issue 6 https://doi.org/10.1158/0008-5472.CAN-14-2103	journal	January 2015
Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies Gallaher, Jill A.; Enriquez-Navas, Pedro M.; Luddy, Kimberly A. Cancer Research, Vol. 78, Issue 8 https://doi.org/10.1158/0008-5472.CAN-17-2649	journal	January 2018
Comparative Pharmacokinetics of Weekly and Every-Three-Weeks Docetaxel Baker, Sharyn D.; Zhao, Ming; Lee, Carlton K. K. Clinical Cancer Research, Vol. 10, Issue 6 https://doi.org/10.1158/1078-0432.CCR-0842-03	journal	March 2004
Evolutionary Determinants of Cancer Greaves, Mel Cancer Discovery, Vol. 5, Issue 8 https://doi.org/10.1158/2159-8290.CD-15-0439	journal	July 2015
Morphisms of reaction networks that couple structure to function Cardelli, Luca BMC Systems Biology, Vol. 8, Issue 1 https://doi.org/10.1186/1752-0509-8-84	journal	January 2014
Tracking the evolution of cancer cell populations through the mathematical lens of phenotype-structured equations Lorenzi, Tommaso; Chisholm, Rebecca H.; Clairambault, Jean Biology Direct, Vol. 11, Issue 1 https://doi.org/10.1186/s13062-016-0143-4	journal	August 2016
Bistability in a Metabolic Network Underpins the De Novo Evolution of Colony Switching in Pseudomonas fluorescens Gallie, Jenna; Libby, Eric; Bertels, Frederic PLOS Biology, Vol. 13, Issue 3 https://doi.org/10.1371/journal.pbio.1002109	journal	March 2015
Spontaneously slow-cycling subpopulations of human cells originate from activation of stress-response pathways Min, Mingwei; Spencer, Sabrina L. PLOS Biology, Vol. 17, Issue 3 https://doi.org/10.1371/journal.pbio.3000178	journal	March 2019
Competing evolutionary paths in growing populations with applications to multidrug resistance Nicholson, Michael D.; Antal, Tibor PLOS Computational Biology, Vol. 15, Issue 4 https://doi.org/10.1371/journal.pcbi.1006866	journal	April 2019
Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous non-small cell lung cancer Craig, Morgan; Kaveh, Kamran; Woosley, Alec PLOS Computational Biology, Vol. 15, Issue 8 https://doi.org/10.1371/journal.pcbi.1007278	journal	August 2019
Stochasticity in the Genotype-Phenotype Map: Implications for the Robustness and Persistence of Bet-Hedging Nichol, Daniel; Robertson-Tessi, Mark; Jeavons, Peter Genetics, Vol. 204, Issue 4 https://doi.org/10.1534/genetics.116.193474	journal	December 2016
Cancer statistics, 2018: Cancer Statistics, 2018 Siegel, Rebecca L.; Miller, Kimberly D.; Jemal, Ahmedin CA: A Cancer Journal for Clinicians, Vol. 68, Issue 1 https://doi.org/10.3322/caac.21442	journal	January 2018
Equivalences between age structured models and state dependent distributed delay differential equations Cassidy, Tyler; Craig, Morgan; R. Humphries, Antony Mathematical Biosciences and Engineering, Vol. 16, Issue 5 https://doi.org/10.3934/mbe.2019270	journal	January 2019

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Phenotype heterogeneity in cancer cell populations

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The role of memory in non-genetic inheritance and its impact on cancer treatment resistance

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