Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Cancer: More Than a Geneticist’s Pandora’s Box

Version 1 : Received: 23 September 2021 / Approved: 24 September 2021 / Online: 24 September 2021 (12:44:34 CEST)

How to cite: Saxena, K.; Subbalakshmi, A.R.; Kulkarni, P.; Jolly, M.K. Cancer: More Than a Geneticist’s Pandora’s Box. Preprints 2021, 2021090432 (doi: 10.20944/preprints202109.0432.v1). Saxena, K.; Subbalakshmi, A.R.; Kulkarni, P.; Jolly, M.K. Cancer: More Than a Geneticist’s Pandora’s Box. Preprints 2021, 2021090432 (doi: 10.20944/preprints202109.0432.v1).

Abstract

Despite identical genetic constitution, a cancer cell population can exhibit phenotypic variations termed as non-genetic/non-mutational heterogeneity. Such heterogeneity – a ubiquitous nature of biological systems – has been implicated in metastasis, therapy resistance and tumour relapse. Here, we review the evidence for existence, sources and implications of non-genetic heterogeneity in multiple cancer types. Stochasticity/ noise in transcription, protein conformation and/or external microenvironment can underlie such heterogeneity. Moreover, the existence of multiple possible cell states (phenotypes) as a consequence of the emergent dynamics of gene regulatory networks may enable reversible cell-state transitions (phenotypic plasticity) that can facilitate adaptive drug resistance and higher metastatic fitness. Finally, we highlight how computational and mathematical models can drive a better understanding of non-genetic heterogeneity and how a systems-level approach integrating mathematical modelling and in vitro/in vivo experiments can map the diverse phenotypic repertoire, and identify therapeutic vulnerabilities of an otherwise clonal cell population.

Keywords

Non-genetic heterogeneity; multistability; drug-tolerant persisters; phenotypic plasticity; biological noise; epithelial-mesenchymal plasticity; PAGE4

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