Abstract The interplay between two recently proposed hallmarks of cancer, namely dedifferentiation/transdifferentiation and altered neuronal signaling, may dictate the spatiotemporal coupling between neurons and astrocytes. Synaptic activity correlates with brain cancer progression and further influences the directionality of metabolites. Through phenotypic plasticity, brain parenchymal cells may dedifferentiate in a manner that determines the directionality of metabolites, thereby altering plasticity and exerting selective pressure on the immune microenvironment within the brain. Therapeutic advancements in brain cancers, including maximizing surgical resection margins and Chimeric Antigen Receptor (CAR) T-cell therapy, have their own limitations. Thus, understanding the interplay between dedifferentiation/transdifferentiation and its role in dictating altered neuronal signaling to modulate the brain tumor microenvironment may provide novel targets for improving prognosis and limiting therapeutic toxicity.

The complexity of cancer requires a comprehensive approach to understand its diverse manifestations and underlying mechanisms. Initially outlined by Hanahan and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a conceptual basis for understanding inherent variability in cancer biology. Recent expansions have further elucidated additional hallmarks, including phenotypic plasticity and senescent cells. The International Agency for Research on Cancer (IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate their carcinogenic potential. We analyzed chemicals of concern for environmental exposure that interact with specific receptors to induce genomic instability, epigenetic alterations, immune suppression, and receptor-mediated effects, thereby contributing to chronic inflammation. Despite their varying degrees of carcinogenicity, these chemicals have similar KCC profiles. Our analysis highlights the pivotal role of receptor binding in activating most other KCCs, underscoring their significance in cancer initiation. Although KCCs are associated with early molecular or cellular events, they do not encompass processes directly linked to full cellular malignancy. Thus, there is a need to integrate clear endpoints that anchor KCCs to the acquisition of a complete malignant phenotype into chemical testing. From the perspective of toxicology and cancer research, an all-encompassing strategy that incorporates both existing and novel KCCs and cancer hallmarks is essential to enable the targeted identification of prevalent carcinogens and facilitate zone-specific prevention strategies. To achieve this goal, collaboration between the KCC and cancer hallmarks communities becomes essential.

Abstract Diffuse intrinsic pontine glioma (DIPG) has a peculiar pathogenesis with canonical Histone variants H3.1/H3.2 wherein Lysine 27 (H3K27) is substituted to methionine (H3K27M). It is restricted to pons and affects young children whereas non canonical H3.3 mutations result in tumours across the midline and affects older children. This discrepancy in the spatiotemporal distribution provides cues to target DIPG. Based on altered neuronal signalling which is a hallmark of cancer, a deeper understanding of neuron tumour interaction may unravel numerous new targets. One such target is light. The restriction of specific spectrum of light may hinder the progression and even the development of tumours in young children. It provides a lucrative therapeutic option which can be implemented merely by blocking a certain spectrum of light with glasses in an otherwise baffling disease. It warrants a deeper understanding of the light exposure on DIPG tumour progression.

Brain tumours continue to be one of the leading causes of childhood mortality related to cancers. Oncohistones such as H3K27M, and H3G34R mutations have been linked to childhood brain tumours. The reason for the incidence of Oncohistone mutation in a developmental setting provides some novel insight for better therapeutics. The maintenance of the progenitor state might be driven by metabolism dictated Oncohistone mutations at the expense of differentiation in the developing brain paving way for tumourigenesis. I propose methods to target metabolic disturbances in the developing brain even prior to the rise of such somatic oncohistone mutations. Additionally, I provide insight into the reason for selective co-mutations that occur with specific Oncohistones in childhood brain tumours providing a rationale for effective therapeutics. In 2021, I proposed neuronal signalling as an Hallmark of cancer, in the context of childhood brain tumours, the nervous system functions as a fulcrum between metabolic reprogramming and the rise of oncohistone mutations leading to epigenetic reprogramming. The nervous system is a lucrative target in inhibiting the metabolic cues that support oncohistones. Metabolic reprogramming may underpin epigenetic reprogramming driving the developing brain across the Bridge of Sighs towards tumourigenesis.

Brain cancers carry a bleak prognosis despite the increase in our understanding of the disease. Brain tumours are in some ways a distinct entity in comparison to other types of tumours due to the distinct type of cell population in the brain tumour microenvironment. Sympathetic and parasympathetic nervous systems have been shown to exert a context-dependent effect on tumourigenesis. In 2021, I proposed neuronal signalling as a hallmark of cancer, albeit resection of specific nerves to hinder tumourigenesis is both challenging and may not result in the desired outcome. In order to add the nervous system to our armamentarium of therapeutic strategies against cancer, we may need to look beyond conventional methods of reducing synaptic plasticity such as with the use of anti-epileptic drugs. One among the strategy I propose is to utilize epigenetics to our advantage. Using lysine demethylase 5 specifically KDM5C to alter the synapticity in the brain tumour microenvironment is one way of exploiting the synaptic plasticity to our advantage against cancers. Additionally, metabolism intertwines the effects mediated by the nervous system which can be exploited to pivot the tumour-promoting effects of the nervous system towards tumour elimination.

Abstract Brain tumours continue to be one of the leading causes of childhood mortality related to cancers. Oncohistones such as H3K27M, and H3G34R mutations have been linked to childhood brain tumours. The reason for the incidence of Oncohistone mutation in a developmental setting provides some novel insight for better therapeutics. The maintenance of the progenitor state might be driven by metabolism dictated Oncohistone mutations at the expense of differentiation in the developing brain paving way for tumourigenesis. I propose methods to target metabolic disturbances in the developing brain even prior to the rise of such somatic oncohistone mutations. Additionally, I provide insight into the reason for selective co-mutations that occur with specific Oncohistones in childhood brain tumours providing a rationale for effective therapeutics. In 2021, I proposed neuronal signalling as an Hallmark of cancer, in the context of childhood brain tumours, the nervous system functions as a fulcrum between metabolic reprogramming and the rise of oncohistone mutations leading to epigenetic reprogramming. The nervous system is a lucrative target in inhibiting the metabolic cues that support oncohistones. Metabolic reprogramming may underpin epigenetic reprogramming driving the developing brain across the Bridge of Sighs towards tumourigenesis.

Diagnosis and treatment of disease demand a sound understanding of the underlying mechanisms, determining any Achilles' heel that can be targeted in effective therapies. Throughout history, this endeavour to decipher the origin and mechanism of transformation of a normal cell into cancer has led to various theories—from cancer as a curse to an understanding at the level of single-cell heterogeneity, meaning even among a single sub-type of cancer there are myriad molecular challenges to overcome. With increasing insight into cancer genetics and biology, the disease has become ever more complex to understand. The complexity of cancer as a disease was distilled into key traits by Hanahan and Weinberg in their seminal ‘Hallmarks of Cancer' reviews. This lucid conceptualization of complex cancer biology is widely accepted and has helped advance cancer therapeutics by targeting the various hallmarks but, with the advancement in technologies, there is greater granularity in how we view cancer as a disease, and the additional understanding over the past decade requires us to revisit the hallmarks of cancer. Based on extensive study of the cancer research literature, we propose four novel hallmarks of cancer, namely, the ability of cells to regress from a specific specialized functional state, epigenetic changes that can affect gene expression, the role of microorganisms and neuronal signalling, to be included in the hallmark conceptualization along with evidence of various means to exploit them therapeutically.

Diagnosis and treatment of disease demand a sound understanding of the underlying mechanisms, determining any Achilles’ heel that can be targeted in effective therapies. Throughout history, this endeavour to decipher the origin and mechanism of transformation of a normal cell into cancer has led to various theories—from cancer as a curse to an understanding at the level of single-cell heterogeneity, meaning even among a single sub-type of cancer there are myriad molecular challenges to overcome. With increasing insight into cancer genetics and biology, the disease has become ever more complex to understand. The complexity of cancer as a disease was distilled into key traits by Hanahan and Weinberg in their seminal ‘Hallmarks of Cancer’ reviews. This lucid conceptualization of complex cancer biology is widely accepted and has helped advance cancer therapeutics by targeting the various hallmarks but, with the advancement in technologies, there is greater granularity in how we view cancer as a disease, and the additional understanding over the past decade requires us to revisit the hallmarks of cancer. Based on extensive study of the cancer research literature, we propose four novel hallmarks of cancer, namely, the ability of cells to regress from a specific specialized functional state, epigenetic changes that can affect gene expression, the role of microorganisms and neuronal signalling, to be included in the hallmark conceptualization along with evidence of various means to exploit them therapeutically.