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Article ; Online: Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm.

Vander Velde, Robert / Shaffer, Sydney / Marusyk, Andriy

2022 Volume 8, Issue 6, Page(s) 456–466

Abstract: Mutational processes and nongenetic phenotypic state transitions represent distinct paradigms for understanding acquired resistance to targeted therapies. While ample empirical evidence supports both paradigms, they are typically viewed as mutually ... ...

Abstract	Mutational processes and nongenetic phenotypic state transitions represent distinct paradigms for understanding acquired resistance to targeted therapies. While ample empirical evidence supports both paradigms, they are typically viewed as mutually exclusive. However, a growing body of evidence points to the multifactorial nature of resistance, where resistant tumor cell phenotypes integrate the influence of multiple mutational and epigenetic changes. This leads to growing calls for a conceptual framework capable of incorporating the effects of genetic and nongenetic mechanisms. Here, we argue that the original Darwinian paradigm centered on the concept of natural selection, rather than its mutation-centric reinterpretation, might provide the optimal backbone for a much-needed synthesis.
MeSH term(s)	Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic ; Humans ; Mutation ; Neoplasms/drug therapy ; Phenotype ; Selection, Genetic
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2022.02.004
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Article ; Online: Selection-driven tumor evolution with public goods leads to patterns of clonal expansion consistent with neutral growth

Jack Edwards / Andriy Marusyk / David Basanta

iScience, Vol 24, Iss 1, Pp 101901- (2021)

2021

Abstract: Summary: Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this ... ...

Abstract	Summary: Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this resource is likely under strong selection. Using agent-based modeling, we explored the interplay between phenotypic strategies centered on gaining access to new space through cell-extrinsic degradation of extracellular matrix barriers and the exploitation of this resource through maximizing cell proliferation. While cell proliferation is a cell-intrinsic property, newly accessed space represents a public good, which can benefit both producers and non-producers. We found that this interplay results in ecological succession, enabling emergence of large, heterogeneous, and highly proliferative populations. Even though in our simulations both remodeling and proliferation strategies were under strong positive selection, their interplay led to sub-clonal architecture that could be interpreted as evidence for neutral evolution, warranting cautious interpretation of inferences from sequencing of cancer genomes.
Keywords	Evolutionary Theories ; Cancer Systems Biology ; Cancer ; Science ; Q
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Selection-driven tumor evolution with public goods leads to patterns of clonal expansion consistent with neutral growth.

Edwards, Jack / Marusyk, Andriy / Basanta, David

iScience

2020 Volume 24, Issue 1, Page(s) 101901

Abstract: Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this resource is ... ...

Abstract	Cancers are the result of eco-evolutionary processes fueled by heritable phenotypic diversification and driven by environmentally dependent selection. Space represents a key growth-limiting ecological resource, the ability to explore this resource is likely under strong selection. Using agent-based modeling, we explored the interplay between phenotypic strategies centered on gaining access to new space through cell-extrinsic degradation of extracellular matrix barriers and the exploitation of this resource through maximizing cell proliferation. While cell proliferation is a cell-intrinsic property, newly accessed space represents a public good, which can benefit both producers and non-producers. We found that this interplay results in ecological succession, enabling emergence of large, heterogeneous, and highly proliferative populations. Even though in our simulations both remodeling and proliferation strategies were under strong positive selection, their interplay led to sub-clonal architecture that could be interpreted as evidence for neutral evolution, warranting cautious interpretation of inferences from sequencing of cancer genomes.
Language	English
Publishing date	2020-12-07
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101901
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Article ; Online: Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance.

Marusyk, Andriy / Janiszewska, Michalina / Polyak, Kornelia

Cancer cell

2020 Volume 37, Issue 4, Page(s) 471–484

Abstract: Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. ... ...

Abstract	Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity.
MeSH term(s)	Drug Resistance, Neoplasm/genetics ; Genetic Heterogeneity ; Humans ; Mutation ; Neoplasm Proteins/genetics ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Phenotype
Chemical Substances	Neoplasm Proteins
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2020.03.007
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Article ; Online: Brain metastasis-associated fibroblasts secrete fucosylated PVR/CD155 that induces breast cancer invasion.

Adhikari, Emma / Liu, Qian / Johnson, Joseph / Stewart, Paul / Marusyk, Viktoriya / Fang, Bin / Izumi, Victoria / Bowers, Kiah / Guzman, Kelly M / Koomen, John M / Marusyk, Andriy / Lau, Eric K

Cell reports

2023 Volume 42, Issue 12, Page(s) 113463

Abstract: Brain metastasis cancer-associated fibroblasts (bmCAFs) are emerging as crucial players in the development of breast cancer brain metastasis (BCBM), but our understanding of the underlying molecular mechanisms is limited. In this study, we aim to ... ...

Abstract	Brain metastasis cancer-associated fibroblasts (bmCAFs) are emerging as crucial players in the development of breast cancer brain metastasis (BCBM), but our understanding of the underlying molecular mechanisms is limited. In this study, we aim to elucidate the pathological contributions of fucosylation (the post-translational modification of proteins by the dietary sugar L-fucose) to tumor-stromal interactions that drive the development of BCBM. Here, we report that patient-derived bmCAFs secrete high levels of polio virus receptor (PVR), which enhance the invasive capacity of BC cells. Mechanistically, we find that HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR, triggering its secretion from bmCAFs. Global phosphoproteomic analysis of BC cells followed by functional verification identifies cell-cell junction and actin cytoskeletal signaling as modulated by bmCAF-secreted, -fucosylated PVR. Our findings delineate a hypoxia- and fucosylation-regulated mechanism by which bmCAFs contribute to the invasiveness of BCBM in the brain.
MeSH term(s)	Female ; Humans ; Brain Neoplasms/pathology ; Breast Neoplasms/pathology ; Cancer-Associated Fibroblasts/pathology ; Fibroblasts/pathology ; Receptors, Virus
Chemical Substances	Receptors, Virus ; poliovirus receptor
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113463
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Article: Somatic clonal evolution: A selection-centric perspective.

Scott, Jacob / Marusyk, Andriy

Biochimica et biophysica acta. Reviews on cancer

2017 Volume 1867, Issue 2, Page(s) 139–150

Abstract: It is generally accepted that the initiation and progression of cancers is the result of somatic clonal evolution. Despite many peculiarities, evolution within populations of somatic cells should obey the same Darwinian principles as evolution within ... ...

Abstract	It is generally accepted that the initiation and progression of cancers is the result of somatic clonal evolution. Despite many peculiarities, evolution within populations of somatic cells should obey the same Darwinian principles as evolution within natural populations, i.e. variability of heritable phenotypes provides the substrate for context-specific selection forces leading to increased population frequencies of phenotypes, which are better adapted to their environment. Yet, within cancer biology, the more prevalent way to view evolution is as being entirely driven by the accumulation of "driver" mutations. Context-specific selection forces are either ignored, or viewed as constraints from which tumor cells liberate themselves during the course of malignant progression. In this review, we will argue that explicitly focusing on selection forces acting on the populations of neoplastic cells as the driving force of somatic clonal evolution might provide for a more accurate conceptual framework compared to the mutation-centric driver gene paradigm. Whereas little can be done to counteract the "bad luck" of stochastic occurrences of cancer-related mutations, changes in selective pressures and the phenotypic adaptations they induce can, in principle, be exploited to limit the incidence of cancers and to increase the efficiency of existing and future therapies. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.
MeSH term(s)	Adaptation, Physiological ; Animals ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Clonal Evolution ; Evolution, Molecular ; Gene Expression Regulation, Neoplastic ; Genetic Fitness ; Genetic Predisposition to Disease ; Heredity ; Humans ; Models, Genetic ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Pedigree ; Phenotype ; Signal Transduction/genetics ; Time Factors
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2017-02-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0304-419X ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0304-419X ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbcan.2017.01.006
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Article ; Online: Author Correction: Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments.

Janiszewska, Michalina / Tabassum, Doris P / Castaño, Zafira / Cristea, Simona / Yamamoto, Kimiyo N / Kingston, Natalie L / Murphy, Katherine C / Shu, Shaokun / Harper, Nicholas W / Del Alcazar, Carlos Gil / Alečković, Maša / Ekram, Muhammad B / Cohen, Ofir / Kwak, Minsuk / Qin, Yuanbo / Laszewski, Tyler / Luoma, Adrienne / Marusyk, Andriy / Wucherpfennig, Kai W /

Wagle, Nikhil / Fan, Rong / Michor, Franziska / McAllister, Sandra S / Polyak, Kornelia

Nature cell biology

2024

Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Published Erratum
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-024-01385-z
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Article: Paracrine enhancement of tumor cell proliferation provides indirect stroma-mediated chemoresistance via acceleration of tumor recovery between chemotherapy cycles.

Miroshnychenko, Daria / Miti, Tatiana / Kumar, Pragya / Miller, Anna / Laurie, Mark / Giraldo, Nathalia / Bui, Marilyn M / Altrock, Philipp M / Basanta, David / Marusyk, Andriy

bioRxiv : the preprint server for biology

2023

Abstract: The ability of tumors to survive therapy reflects both cell-intrinsic and microenvironmental mechanisms. Across many cancers, including triple-negative breast cancer (TNBC), a high stroma/tumor ratio correlates with poor survival. In many contexts, this ... ...

Abstract	The ability of tumors to survive therapy reflects both cell-intrinsic and microenvironmental mechanisms. Across many cancers, including triple-negative breast cancer (TNBC), a high stroma/tumor ratio correlates with poor survival. In many contexts, this correlation can be explained by the direct reduction of therapy sensitivity by stroma-produced paracrine factors. We sought to explore whether this direct effect contributes to the link between stroma and poor responses to chemotherapies. Our
Language	English
Publishing date	2023-07-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.07.527543
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Article ; Online: Questions to guide cancer evolution as a framework for furthering progress in cancer research and sustainable patient outcomes.

Somarelli, Jason A / DeGregori, James / Gerlinger, Marco / Heng, Henry H / Marusyk, Andriy / Welch, Danny R / Laukien, Frank H

Medical oncology (Northwood, London, England)

2022 Volume 39, Issue 9, Page(s) 137

Abstract: We appear to be faced with 'two truths' in cancer-one of major advances and successes and another one of remaining short-comings and significant challenges. Despite decades of research and substantial progress in treating cancer, most patients with ... ...

Abstract	We appear to be faced with 'two truths' in cancer-one of major advances and successes and another one of remaining short-comings and significant challenges. Despite decades of research and substantial progress in treating cancer, most patients with metastatic cancer still experience great suffering and poor outcomes. Metastatic cancer, for the vast majority of patients, remains incurable. In the context of advanced disease, many clinical trials report only incremental advances in progression-free and overall survival. At the same time, the breadth and depth of new scientific discoveries in cancer research are staggering. These discoveries are providing increasing mechanistic detail into the inner workings of normal and cancer cells, as well as into cancer-host interactions; however, progress remains frustratingly slow in translating these discoveries into improved diagnostic, prognostic, and therapeutic interventions. Despite enormous advances in cancer research and progress in progression-free survival, or even cures, for certain cancer types-with earlier detection followed by surgical, adjuvant, targeted, or immuno- therapies, we must challenge ourselves to do even better where patients do not respond or experience evolving therapy resistance. We propose that defining cancer evolution as a separate domain of study and integrating the concept of evolvability as a core hallmark of cancer can help position scientific discoveries into a framework that can be more effectively harnessed to improve cancer detection and therapy outcomes and to eventually decrease cancer lethality. In this perspective, we present key questions and suggested areas of study that must be considered-not only by the field of cancer evolution, but by all investigators researching, diagnosing, and treating cancer.
MeSH term(s)	Humans ; Neoplasms/diagnosis ; Neoplasms/therapy ; Prognosis
Language	English
Publishing date	2022-07-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1201189-7
ISSN	1559-131X ; 0736-0118 ; 1357-0560
ISSN (online)	1559-131X
ISSN	0736-0118 ; 1357-0560
DOI	10.1007/s12032-022-01721-z
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Article ; Online: Cancer: Clonal cooperation.

Polyak, Kornelia / Marusyk, Andriy

Nature

2014 Volume 508, Issue 7494, Page(s) 52–53

MeSH term(s)	Animals ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Female ; Wnt1 Protein/metabolism
Chemical Substances	Wnt1 Protein ; Wnt1 protein, mouse
Language	English
Publishing date	2014-04-02
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/508052a
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