Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting organotropic metastasis

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. Whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their neural crest, sympatho-adrenal origin remains unclear. Here, we identified the transcriptional signature distinguishing LR-NBs from HR-NBs, which consists mainly of genes that belong to the core sympatho-adrenal developmental program and are associated with favorable patient prognosis and with diminished disease progression. Gain- and loss-of-function experiments revealed that the top candidate gene of this signature, Neurexophilin-1 (NXPH1), has a dual impact on NB cell behavior in vivo: whereas NXPH1 and its receptor α-NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit organotropic colonization and metastasis. As suggested by RNA-seq analyses, these effects might result from the ability of NXPH1/α-NRXN signalling to restrain the conversion of NB cells from an adrenergic state to a mesenchymal one. Our findings thus uncover a transcriptional module of the sympatho-adrenal program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/α-NRXN signaling as a promising target to treat HR-NBs.This work was supported by grants from the Ministerio de Ciencia e Innovacion, Gobierno de España (MCINN; BFU2016-81887-REDT and BFU2016-77498-P) and the Asociación Española Contra el Cancer (AECC CI_2016) to EM, from the Fondo de Investigación en Salud (FIS) - Instituto de salud Carlos III (PI14/00038) and the NEN association (Association of Families and Friends of Patients with Neuroblastoma) to CL, from the Instituto de Salud Carlos III-FSE (MS17/00037; PI18/00014; PI21/00020) to TC-T, from Instituto de Salud Carlos III (CP22/00127, co-funded by European Social Fund “Investing in your future”) to BMJ, from the Agence Nationale pour la Recherche (ANR-17-CE14-0023-01, ANR-17-CE14-0009-02) and the city of Paris (Emergence program) to ELG, from ISCIII-FEDER (CP13/00189 and CPII18/00009) to AMC. LF received a PhD fellowship from the Spanish Ministry of Science, Education and Universities (FPU AP2012-2222). LT-D was funded by a FPI Fellowship (PRE2019-088005). GLD was supported by the Asociación Española Contra el Cancer (AECC #AIO14142105LED)

P53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription. The failure of chemotherapy in colorectal cancer is currently unclear. Here, the authors show that upon sub-lethal dose of chemotherapy wild-type p53 colorectal cancers acquire a quiescence-like phenotype and a YAP-dependent fetal-like intestinal stem cell state associated with a higher metastatic activity and poor prognosis in patients

Zeb1 en las células estrelladas del páncreas: implicación en la oncogénesis pancreática dependiente de Kras

[spa] El factor de transcripción Zeb1 tiene un papel crucial en la oncogénesis mediada por Kras. En el adenocarcinoma ductal de páncreas (ACDP), Zeb1 muestra una elevada expresión en los miofibroblastos, la cual se correlaciona con un peor pronóstico de la enfermedad. Ya que Kras es una de las mutaciones clave para el inicio y desarrollo del ACDP, el objetivo de esta tesis es estudiar la función de Zeb1 en la progresión del ACDP, así como definir el papel en la oncogénesis pancreática de los miofibroblastos que expresan Zeb1. Para ello, se han utilizado modelos murinos con mutaciones en KrasG12D y p53R172H condicionadas al páncreas mediante el alelo Pdx1-Cre (KPC); estos ratones se han cruzando con ratones haploinsuficientes en Zeb1 para obtener animales KPC;Z+/-. Los resultados muestran ACDP en todos los ratones KPC;Z+/+ de 20 semanas, mientras que los ratones KPC;Z+/- de la misma edad exhiben lesiones precursoras de bajo grado, aunque terminan desarrollando tumor a edad avanzada. También se observa que la expresión de Zeb1 en las células estrelladas del páncreas (CEPs) ocurre en las primeras estapas de la carcinogénesis, y que la haploinsuficiencia de Zeb1 retarda la activación de las CEPs y la generación de un estroma colaborativo con el tumor. Por otro lado, la heterocigosis de Zeb1 en las CEPs reprime su perfil activado, impide su actividad migratoria y proliferativa, atenúa sus características pro-tumorales y condiciona en estas células la regulación negativa de vías de señalización implicadas en el cáncer de páncreas. Además, el medio condicionado de CEPs con expresión completa de Zeb1 incrementa la actividad de Ras en células acinares y neoplásicas portadoras del oncogén Kras; este efecto no se observa al utilizar medio condicionado de CEPs haploinsuficientes en Zeb1, lo cual revela la existencia de un eje de comunicación intercelular entre CEPs con expresión de Zeb1 y células neoplásicas con Kras mutado. Los resultados de esta tesis permiten concluir que la expresión de Zeb1 en los miofibroblastos del estroma posibilitan la colaboración heterotípica con el compartimento epitelial portador del oncogén Kras, promoviendo la oncogénesis pancreática

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCOR CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN

p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.This work was supported by the Instituto de Salud Carlos III-FSE (nos. MS17/00037 and PI18/00014) and the Cancer Research Institute, Clinic and Laboratory Integration Program (grant no. CRI2477 to T.C.-T). We also thank the AECC LAB (grant no. LABAE19007CELI) and the FERO foundation (to T.C.-T). This work was also supported by ISCIII (CIBERONC nos. CB16/12/00481, CB16/12/00241, PI18/00006 and PI21/00002), Generalitat de Catalunya (no. 2017 SGR 507) and the European Community through the Regional Development Funding Program to J. Albanell. Y.K. is supported by the Brewster Foundation, the Breast Cancer Research Foundation, the Susan G. Komen Foundation and the American Cancer Society. J. Arribas is funded by the Breast Cancer Research Foundation (no. BCRF-20-08), Instituto de Salud Carlos III (no. PI19/01181), Asociación Española Contra el Cáncer (no. GCAEC19017ARRI) and Fundación BBVA (no. CAIMI VHIO-FBBVA 2018-2021). M.M.A. is funded by MICINN and the Spanish Government (no. PGC2018-094091-B-I00). D.C. was funded by Instituto de Salud Carlos III (no. JR1800003). S.M. is funded by PERIS (no. SLT006/17/00040). The wotk of R.R.G. is funded by MICINN, the Spanish Government (no. PID2019-104948RB-I00) and the BBVA Foundation. S.B and J.P. acknowledge support from the Spanish Ministry of Science, the EMBL partnership and the CESO and CERCA Program