1 Introduction

Cancer is a complex and heterogeneous disease characterized not merely by uncontrolled cell growth but also by the remarkable adaptability of cancer cells to survive under various stress conditions (Hanahan 2022; Swanton et al. 2024; Zhang et al. 2024). This adaptability, termed cellular plasticity, is a fundamental hallmark of cancer cells that significantly contributes to treatment resistance, tumor metastasis, and disease recurrence (Pérez-González et al. 2023). Cellular plasticity is a major driving force behind tumor heterogeneity, where distinct subpopulations of cancer cells coexist within the same tumor, exhibiting different phenotypic and functional properties, such as highly proliferative or metastatic phenotypes (Gupta et al. 2019). This heterogeneity poses a significant obstacle to effective cancer treatment, as it increases the likelihood of treatment-resistant subpopulations emerging and contributing to disease relapse.

Oncogenes, the driver genes that promote uncontrolled cell proliferation, are have long been recognized as key drivers of cellular transformation and tumorigenesis (Felsher 2003). Therefore, researchers have developed diverse strategies targeting oncogenes at DNA, RNA, and protein levels to combat cancer, including genome editing, RNA interference, small molecule inhibitors, and immunotherapies. This multi-pronged approach aims to provide comprehensive and personalized cancer treatments by targeting oncogene expression, activity, and signaling pathways, potentially overcoming resistance mechanisms and improving patient outcomes. Nevertheless, accumulating evidence demonstrates that the activation of certain oncogenes can induce processes like epithelial-to-mesenchymal transition (EMT) in tumor cells, conferring enhanced invasive and metastatic capabilities (Grunert et al. 2003). Paradoxically, some studies have revealed that targeting oncogenes to inhibit tumor cell proliferation can unexpectedly promote metastasis. Oncogenes, such as CREB1 (cAMP Response Element Binding Protein 1), MYC (MYC Proto-Oncogene, bHLH Transcription Factor), and so on, can hijack and dysregulate various cellular pathways and processes, leading to the induction of cellular plasticity (Li et al. 2022; Liu et al. 2012). These oncogenes can activate transcriptional programs that govern EMT, stem cell properties, and metabolic reprogramming, all of which contribute to the acquisition of diverse and resilient cancer cell states. This phenomenon underscores the importance of considering tumor cell plasticity and its influence on the biological behavior of the tumor when designing and implementing tumor treatment strategies.

In this review, we will focus on the core concept of "targeting oncogenes induces a phenotypic shift between proliferation and metastasis", and investigate into the biology of oncogenes that promote cell proliferation but inhibit metastasis, explore the rationale behind combination therapies, and discuss the current strategies and emerging directions in the field. By conducting an in-depth analysis of the available evidence and exploring the potential of these innovative approaches, we aim to provide a comprehensive overview of the state of the art in targeting complex oncogenes and improving cancer treatment outcomes.

2 Mechanisms of oncogene-induced cellular plasticity

2.1 Overview of cellular plasticity in cancer

Cellular plasticity in cancer encompasses a wide range of phenotypic and metabolic adaptations that allow cancer cells to survive and thrive in various microenvironmental conditions. This plasticity can manifest in different forms, including stem-like properties, EMT, metabolic reprogramming and quiescence and dormancy (Bergers et al., 2021; Brabletz 2012; Pérez-González et al. 2023; Schwitalla 2014). These states result from a dynamic balance between proliferative and metastatic phenotypes (Fig. 1).

Fig. 1
figure 1

Changes of proliferation rate and metastatic potential during tumor progression

Full size image

Cancer cells can acquire stem cell-like characteristics, such as self-renewal capacity, multi-lineage differentiation potential, slow proliferation rate and increased resistance to therapeutic interventions (Huyghe et al. 2024). These cancer stem cells (CSCs) are believed to play a crucial role in tumor metastasis, and disease recurrence. EMT is a process through which epithelial cells lose their cell-cell adhesion and polarity, transitioning into a more invasive and migratory mesenchymal phenotype (Brabletz et al. 2018). EMT has been implicated in cancer metastasis, as well as the acquisition of stem-like properties and treatment resistance. Cancer cells can rewire their metabolic pathways to adapt to nutrient-deprived or hypoxic conditions within the tumor microenvironment (Bergers et al., 2021). This metabolic plasticity involves shifts in energy production pathways, such as increased glycolysis, glutaminolysis, or oxidative phosphorylation, enabling cancer cells to meet their biosynthetic and energetic demands under stress. In response to specific environmental cues or therapeutic interventions, cancer cells can enter a quiescent or dormant state, characterized by reduced proliferation and metabolic activity (Giancotti 2013). This cellular plasticity allows cancer cells to persist in a treatment-resistant state, potentially contributing to tumor recurrence and metastasis at later stages.

The remarkable ability of cancer cells to undergo these diverse phenotypic and metabolic transitions is a fundamental characteristic of cellular plasticity, enabling tumor cells to adapt, survive, and propagate in various microenvironmental contexts.

2.2 Oncogenes involved in inducing cellular plasticity

The regulatory pattern of genes in cell proliferation and metastasis is a sophisticated orchestration of molecular events that determine the behavior of cancer cells. This intricate balance is characterized by the dual roles’ genes can play in either promoting or inhibiting these processes. Based on the pattern of genes simultaneously regulating cell proliferation and metastasis, genes can be classified into four types. The first category, Type I genes, often oncogenes, are well-known for their role in driving cellular transformation, with numerous studies documenting their ability to promote both cell proliferation and metastasis (Buscail et al. 2020; Ciardiello et al., 2008; Gilkes et al. 2014) (Fig. 2, Type I). In contrast, Type II genes function as inhibitors for both processes (Fig. 2, Type II). Typically, these are tumor suppressor genes that are crucial in maintaining normal cell cycle control and preventing the development of metastatic capabilities in cancer cells. Meanwhile, accumulating evidence suggests that certain oncogenes also play a critical role in inducing and maintaining cellular plasticity in cancer cells by regulating the switch between proliferation and metastasis. Specifically, Type III genes possess the remarkable capacity to enhance cell proliferation while concurrently restraining cell metastasis (Li et al. 2022; Liu et al. 2012; Rossi et al. 2022) (Fig. 2, Type III). Lastly, Type IV genes are those that inhibit cell proliferation but, in a counterintuitive manner, promote metastasis (Fig. 2, Type IV).

Fig. 2
figure 2

The regulatory pattern of genes in cell proliferation and metastasis

Full size image

In these types of genes, the oncogenic properties of Type III genes are particularly noteworthy. Inhibiting these genes, though effective in suppressing tumor cell proliferation, exacerbates the fatal metastatic potential of tumor cells. Many research has found that certain oncogenes mainly regulate tumor metastasis by negatively regulating EMT and integrin-related processes.

2.2.1 Oncogenes promote proliferation while inhibiting metastasis by regulating EMT

EMT is a process enabling epithelial cells to undergo profound alterations in morphology and behavior, culminating in the acquisition of a migratory and invasive phenotype, characteristic of cancer metastasis. While numerous oncogenes have been identified as enhancers of tumor metastasis through the promotion of EMT, a subset of oncogenes, such as CREB1, MYC and FBXO22 (F-box protein 22), has been observed to concurrently facilitate proliferation while inhibiting EMT (Fig. 3). This underscores the intricate and occasionally contradictory roles these oncogenes play in tumor biology.

Fig. 3
figure 3

The mechanisms by which oncogenes can concurrently regulate both cell proliferation and metastasis

Full size image

CREB1, a transcription factor with pleiotropic functions, exemplifies this duality (Li et al. 2022). In colorectal cancer, CREB1 activates the transcription of CCAT1 (colon cancer associated transcript 1), which upregulates MYC, a potent oncogene. This axis drives cell cycle progression and enhances cell proliferation. Yet, CREB1 also suppresses the NF-κB (Nuclear factor kappa B) pathway, a key regulator of EMT, thereby inhibiting the migratory and invasive capabilities of cancer cells (Fig. 3). Additionally, as a pivotal responder to the second messenger cAMP, CREB1 potentially contributes to metastasis inhibition through the cAMP-PKA-CREB1 signaling cascade. For example, elevated intracellular cAMP levels, along with subsequent PKA activation, induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells by phosphorylating histone demethylase PHF2 (PHD Finger Protein 2) (Pattabiraman et al. 2016). In pancreatic cancer cells, Zimmerman et al. demonstrated that cAMP-elevating drugs hindered both basal and TGF-β-directed pancreatic ductal adenocarcinoma (PDAC) cell migration and invasion (Zimmerman et al. 2015). These findings underscore the pivotal role of CREB1 in maintaining the delicate balance between tumor growth and metastatic potential.

Similarly, FBXO22, a component of the SCF ubiquitin ligase complex, promotes cell proliferation in breast cancer, particularly in triple-negative breast cancer cells (Sun et al. 2022), primarily promoting cell proliferation without affecting the regulation of integrin proteins and their associated suppression of metastasis (Liu et al. 2012).

Secondly, the heterogeneity of cancer, both between and within tumors, adds another layer of complexity to the design and implementation of precision therapies. The application of single-cell genomics, transcriptomics, and proteomics can provide valuable insights into the heterogeneity of plasticity phenotypes within a tumor. By identifying and characterizing specific subpopulations exhibiting different plasticity states, researchers can develop targeted strategies tailored to each subpopulation.

The future of cancer treatment lies in the continued exploration of precision therapies and the development of novel strategies to address the challenges posed by oncogene-induced cellular plasticity. Advances in genomics, proteomics, and bioinformatics will be instrumental in identifying new therapeutic targets and understanding the complex interplay between oncogenes and cellular plasticity pathways. Personalized medicine approaches, tailored to individual patient profiles, will also play a significant role in optimizing combination therapies, potentially leading to improved patient outcomes and a new era in cancer treatment.

During the primary tumor stage, tumor cells exhibit robust proliferative capacity but limited metastatic potential. As the tumor cells proliferate, due to factors such as intrinsic genetic mutations in tumor cells, changes in the extrinsic tumor microenvironment, and drugs targeting oncogenes, some tumor cells develop stem-like properties, undergo EMT, metabolic reprogramming, or enter dormancy through plasticity regulation. Consequently, the proliferative capacity of these tumor cells diminishes while their metastatic potential is augmented. Following vascular invasion, these plasticity-regulated cells infiltrate the bloodstream and seed metastatic tumor foci in distant tissues.

Based on the pattern of genes simultaneously regulating cell proliferation and metastasis, genes can be classified into four types: Type I, genes that concurrently promote proliferation and metastasis, such as HIF1a, EGFR, and KRAS; Type II, genes that simultaneously inhibit proliferation and metastasis, such as TP53, PTEN, and RB; Type III, genes that promote proliferation but inhibit metastasis, such as CREB1, MYC, and PHGDH; Type IV, genes that inhibit proliferation but promote metastasis, such as TGF-β, SNAIL and CDKN1A.

Type III genes facilitate cell proliferation while concurrently restraining cell metastasis. For instance, CRBE1, FBXO22, TMEM16A, SnoN, and MAZ bolster cell proliferation by fostering the cell cycle progression, yet they concurrently hinder cell metastasis by impeding the EMT process. Additionally, MYC and PHGDH regulate cell proliferation capacity (P) by governing the cell cycle and serine synthesis, respectively. Simultaneously, they transcriptionally suppress integrin proteins, diminishing cell adhesion to the extracellular matrix and fostering cell metastatic potential (M).

Initially, primary tumor cells exhibit robust proliferative capacity (P), yet their metastatic potential (M) remains relatively constrained. Targeted therapy aimed at inhibiting oncogenes can partially curb the proliferative capacity of tumor cells. However, due to tumor cell plasticity, certain cells undergo EMT, metabolic reprogramming, and other alterations, thereby augmenting their metastatic potential and culminating in the development of metastatic tumors. Consequently, solely targeting tumor cell proliferation with such therapies may prove inadequate for complete cancer eradication. Combination therapy endeavors to concurrently address pivotal drivers of induced cellular plasticity, including oncogenes, EMT transcription factors, and metabolic enzymes. By collectively targeting these critical factors, it is anticipated to more effectively suppress both tumor cell proliferation and metastatic potential, ultimately precipitating tumor cell demise.