RESUMEN
Stem cells play pivotal roles in maintaining intestinal homeostasis, orchestrating regeneration, and in key steps of colorectal cancer (CRC) initiation and progression. Intriguingly, adult stem cells are reduced during many of these processes. On the contrary, primitive fetal programs, commonly detected in development, emerge during tissue repair, CRC metastasis, and therapy resistance. Recent findings indicate a dynamic continuum between adult and fetal stem cell programs. We discuss critical mechanisms facilitating the plasticity between stem cell states and highlight the heterogeneity observed upon the appearance of fetal-like states. We focus on therapeutic opportunities that arise by targeting fetal-like CRC cells and how those concepts can be translated into the clinic.
Asunto(s)
Neoplasias Colorrectales , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/terapia , Humanos , Animales , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células Madre Fetales/metabolismoRESUMEN
Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Ratones , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Desequilibrio Alélico , Genes ras , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Mutación , Microambiente Tumoral/genéticaRESUMEN
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.
Asunto(s)
Carcinogénesis/metabolismo , Neoplasias del Colon/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Carcinogénesis/patología , Diferenciación Celular , Supervivencia Celular , Colon/patología , Neoplasias del Colon/genética , Células Epiteliales/metabolismo , Feto/patología , Inflamación/patología , Estimación de Kaplan-Meier , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos C57BL , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Proteínas Señalizadoras YAPRESUMEN
Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. SIGNIFICANCE: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Carcinoma Ductal Pancreático/prevención & control , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pancreáticas/prevención & control , Microambiente Tumoral , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/inmunología , Animales , Apoptosis , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias PancreáticasRESUMEN
Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Regiones no Traducidas 5'/genética , Sistema de Transporte de Aminoácidos ASC/metabolismo , Animales , Carcinogénesis/patología , Proliferación Celular , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Glutamina/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Estimación de Kaplan-Meier , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor/metabolismo , Metástasis de la Neoplasia , Oncogenes , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear whether statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporter-lowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen. SIGNIFICANCE: Cancer cells induce specific metabolic pathways to alleviate the increased oxidative stress caused by statin treatment, and targeting one of these pathways synergizes with statins to produce a robust antitumor response.See related commentary by Cordes and Metallo, p. 151.