Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance

Sep 21, 2026

Cancer cell plasticity enables cancer cells to shift among distinct states and phenotypes in response to their surroundings, driving greater tumor diversity and fostering drug resistance. The review examines cellular, molecular, and genetic mechanisms, linking plasticity with epithelial–mesenchymal transition and stem cell–like features. It addresses the persistent challenge of therapy-induced resistance despite targeted-therapy advances, covering epigenetic changes, signaling rewiring, and microenvironmental interactions. It also evaluates counterstrategies, including pathway targeting and combination therapies, aiming to improve treatment efficacy and precision medicine outcomes.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages32

Reading Time1 h 21 min

AccessFree to download

Abstract

Keywords

1 Introduction

Cancer and Metastasis Reviews (2024) 43:197–228 [https://doi.org/10.1007/s10555-024-10172-z](https://doi.org/10.1007/s10555-024-10172-z) Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance Gh Rasool Bhat1 · Itty Sethi2 · Hana Q. Sadida3 · Bilal Rah4 · Rashid Mir5 · Naseh Algehainy5 · Ibrahim Altedlawi Albalawi6 · Tariq Masoodi7 · Gowtham Kumar Subbaraj8 · Farrukh Jamal9 · Mayank Singh10 · Rakesh Kumar11 · Muzafar A. Macha12 · Shahab Uddin13,14 · Ammira S. Al‑Shabeeb Akil3 · Mohammad Haris14,15 · Ajaz A. Bhat3 Received: 1 October 2023 / Accepted: 24 January 2024 / Published online: 8 February 2024 © The Author(s) 2024 Abstract Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell–like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes. Keywords Cancer cell plasticity · Cancer stem cells · Epithelial-mesenchymal transition · Tumor heterogeneity · Drug resistance · Targeted therapies 1 Introduction Cancer stands as one of the most formidable health challenges of our time, driven by the unrestrained growth and division of abnormal cells within the body. This unwarranted proliferation infiltrates and damages healthy tissues, culminating in a diverse spectrum of disorders, each identified by the cell or tissue type of origin. With a projected statistic that one in every four individuals over the age of 65 will have battled cancer by 2040, it is underscored as a leading global cause of death [1] . Extended author information available on the last page of the article This multifaceted disease evolves through numerous steps, with many malignant pathways leading to diverse tumor types and subtypes. Each pathway includes unique aberrations and consequentially acquired traits necessary for overcoming tissue-specific barriers in specific tumorigenesis pathways [2, 3] . However, one critical aspect threading through this complexity is cancer cell plasticity. This phenomenon allows cancer cells to adapt and change, making them even more resilient and difficult to treat. Cancer cell plasticity is closely related to t

FAQs

What is cancer cell plasticity and why does it matter?

Cancer cell plasticity is the ability of cancer cells to change in response to their environment. It contributes to tumor diversity and therapy resistance, making cancers more difficult to treat.

Which biological processes are closely linked to cancer cell plasticity?

The review connects cancer cell plasticity with epithelial–mesenchymal transition and the acquisition of stem cell–like features. These processes are described as pivotal for tumor development and progression.

What mechanisms and factors help cancer cells maintain plasticity?

Mechanisms described include epigenetic modifications, alterations in signaling pathways such as Wnt and Notch, and environmental interactions involving the tumor microenvironment (e.g., hypoxia-related methylation changes).

How can therapy strategies counteract cancer cell plasticity?

The review discusses targeting specific cellular pathways and using combination therapies. These strategies are presented as ways to enhance treatment efficacy and mitigate therapy resistance.

Sep 21, 2026

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