RESUMEN
Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance1. In addition to genetic mutations2, recent research has identified a role for non-genetic plasticity in transient drug tolerance3 and the acquisition of stable resistance4,5. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.
Asunto(s)
Adaptación Fisiológica , Plasticidad de la Célula , Resistencia a Antineoplásicos , Neoplasias , Femenino , Humanos , Ratones , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/genética , Línea Celular Tumoral , Plasticidad de la Célula/efectos de los fármacos , Plasticidad de la Célula/genética , Reprogramación Celular/efectos de los fármacos , Reprogramación Celular/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Epigénesis Genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , FenotipoRESUMEN
Polychlorinated biphenyls are ubiquitous environmental contaminants linkedc with peripheral immune and neural dysfunction. Neuroimmune signaling is critical to brain development and later health; however, effects of PCBs on neuroimmune processes are largely undescribed. This study extends our previous work in neonatal or adolescent rats by investigating longer-term effects of perinatal PCB exposure on later neuroimmune responses to an inflammatory challenge in adulthood. Male and female Sprague-Dawley rats were exposed to a low-dose, environmentally relevant, mixture of PCBs (Aroclors 1242, 1248, and 1254, 1:1:1, 20⯵g / kg dam BW per gestational day) or oil control during gestation and via lactation. Upon reaching adulthood, rats were given a mild inflammatory challenge with lipopolysaccharide (LPS, 50⯵g / kg BW, ip) or saline control and then euthanized 3â¯hours later for gene expression analysis or 24â¯hours later for immunohistochemical labeling of Iba1+ microglia. PCB exposure did not alter gene expression or microglial morphology independently, but instead interacted with the LPS challenge in brain region- and sex-specific ways. In the female hypothalamus, PCB exposure blunted LPS responses of neuroimmune and neuromodulatory genes without changing microglial morphology. In the female prefrontal cortex, PCBs shifted Iba1+ cells from reactive to hyperramified morphology in response to LPS. Conversely, in the male hypothalamus, PCBs shifted cell phenotypes from hyperramified to reactive morphologies in response to LPS. The results highlight the potential for long-lasting effects of environmental contaminants that are differentially revealed over a lifetime, sometimes only after a secondary challenge. These neuroimmune endpoints are possible mechanisms for PCB effects on a range of neural dysfunction in adulthood, including mental health and neurodegenerative disorders. The findings suggest possible interactions with other environmental challenges that also influence neuroimmune systems.
Asunto(s)
Lipopolisacáridos , Microglía , Bifenilos Policlorados , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-Dawley , Caracteres Sexuales , Animales , Femenino , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Bifenilos Policlorados/toxicidad , Ratas , Lipopolisacáridos/toxicidad , Embarazo , Contaminantes Ambientales/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/crecimiento & desarrolloRESUMEN
Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis.
Asunto(s)
Neoplasias , Microambiente Tumoral , Animales , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Interferones , Ratones , Neoplasias/patología , Microambiente Tumoral/genéticaRESUMEN
Exposure to environmental contaminants early in life can have long lasting consequences for physiological function. Polychlorinated biphenyls (PCBs) are a group of ubiquitous contaminants that perturb endocrine signaling and have been associated with altered immune function in children. In this study, we examined the effects of developmental exposure to PCBs on neuroimmune responses to an inflammatory challenge during adolescence. Sprague Dawley rat dams were exposed to a PCB mixture (Aroclor 1242, 1248, 1254, 1:1:1, 20 µg/kg/day) or oil control throughout pregnancy, and adolescent male and female offspring were injected with lipopolysaccharide (LPS, 50 µg/kg, ip) or saline control prior to euthanasia. Gene expression profiling was conducted in the hypothalamus, prefrontal cortex, striatum, and midbrain. In the hypothalamus, PCBs increased expression of genes involved in neuroimmune function, including those within the nuclear factor kappa b (NF-κB) complex, independent of LPS challenge. PCB exposure also increased expression of receptors for dopamine, serotonin, and estrogen in this region. In contrast, in the prefrontal cortex, PCB exposure blunted or induced irregular neuroimmune gene expression responses to LPS challenge. Moreover, neither PCB nor LPS exposure altered expression of neurotransmitter receptors throughout the mesocorticolimbic circuit. Almost all effects were present in males but not females, in agreement with the idea that male neuroimmune cells are more sensitive to perturbation and emphasizing the importance of studying both male and female subjects. Given that altered neuroimmune signaling has been implicated in mental health and substance abuse disorders that often begin during adolescence, these results highlight neuroimmune processes as another mechanism by which early life PCBs can alter brain function later in life.