RESUMEN
Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.
Asunto(s)
Neoplasias Colorrectales , Tetraploidía , Humanos , Proteínas de la Ataxia Telangiectasia Mutada/genética , Transducción de Señal , Daño del ADN , Reparación del ADN , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.
Asunto(s)
Neoplasias , Microambiente Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de PrecisiónRESUMEN
Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant CRC cells (LIM1215 and OXCO2) but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 and OXCO2 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells both in vitro and in vivo. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.
Asunto(s)
Cetuximab , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Receptores ErbB , Ácido Láctico , Transportadores de Ácidos Monocarboxílicos , Simportadores , Humanos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Simportadores/metabolismo , Simportadores/genética , Ácido Láctico/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Cetuximab/farmacología , Línea Celular Tumoral , Animales , Ratones , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Glucólisis/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular/efectos de los fármacosRESUMEN
Extracellular acidification has been shown to be an important characteristic of invasive tumors, as it promotes invasion and migration but also resistance to treatments. Targeting transporters involved in the regulation of tumor pH constitutes a promising anti-tumor approach, as it would disrupt cellular pH homeostasis and negatively impact tumor growth. In this study, we evaluated the impact of syrosingopine, an inhibitor of MCT1 and MCT4, as a modulator of tumor metabolism and extracellular acidification in human breast cancer (MDA-MB-231) and pharyngeal squamous cell carcinoma (FaDu) cell models. In both models in vitro, we observed that exposure to syrosingopine led to a decrease in the extracellular acidification rate, intracellular pH, glucose consumption, lactate secretion and tumor cell proliferation with an increase in the number of late apoptotic/necrotic cells. However, in vivo experiments using the MDA-MB-231 model treated with a daily injection of syrosingopine did not reveal any significant change in extracellular pH (pHe) (as measured using CEST-MRI) or primary tumor growth. Overall, our study suggests that targeting MCT could lead to profound changes in tumor cell metabolism and proliferation, and it warrants further research to identify candidates without off-target effects.
RESUMEN
Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member 4 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed by epithelial ductal cells. Functionally, SLC4A4 inhibition in PDAC cancer cells mitigates the acidosis of the TME due to bicarbonate accumulation in the extracellular space and a decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and breaches macrophage-mediated immunosuppression, thus inhibiting tumor growth and metastases. In addition, Slc4a4 targeting in combination with immune checkpoint blockade is able to overcome immunotherapy resistance and prolong survival. Overall, our data propose SLC4A4 as a therapeutic target to unleash an antitumor immune response in PDAC.