Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography

Cassol, Franca; Portal, L. Fernández; Richelme, Sylvie; Dupont, Mathieu; Boursier, Yannick; Arechederra, María; Auphan-Anezin, Nathalie; Chasson, Lionel; Laprie, Caroline; Fernandez, Samantha; Balasse, Laure; Lamballe, Fabienne; Dono, Rosanna; Guillet, Benjamin; Lawrence, Toby; Morel, C.; Maina, Flavio

doi:10.1016/j.isci.2019.10.015

Cited by 10 publications

(18 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the analysis performed using databases also revealed an increase in C3G mRNA levels in livers from DEN treated mice ( Figure S1C ). Next, we evaluated C3G expression levels in liver tumors and HCC cell lines (mHCCs) derived from the Alb-R26 Met mouse HCC model induced by moderately increased MET levels in hepatocytes, which recapitulates the proliferative subtype of human HCC [ 33 , 34 , 35 , 36 , 37 ]. As shown in Figure 1 E, C3G overexpression was found in all tumors as compared to normal liver tissue.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we employed in vitro and in vivo approaches to explore the role of C3G in HCC. We used human HCC cell lines and mouse HCC cell lines derived from the Alb-R26 Met mouse HCC model, proven to be clinically relevant [ 33 , 34 , 35 , 36 , 37 ]. In addition, we have analyzed data from human HCC patient samples available in public databases to strengthen the potential relevance of C3G in HCC.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

Sequera

Bragado

Manzano

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

Sequera

Bragado

Manzano

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…The vulnerability of the mammary gland to a slight increase in MET levels resembles the susceptibility of the liver we reported in previous studies. [28,[57][58][59] The vulnerability of the mammary gland and the liver is contrasted by a remarkable resilience of other tissues, in which a tumorigenic event requires additional genetic alterations, as reported for malignant peripheral nerve sheath tumors. [60] Whether such a mild MET perturbation in the mammary gland occurs in specific subgroups of women and/or physiological contexts and can The second major finding of this work is that combinatorial inhibition of WEE1 and BCL-XL kills a panel of heterogeneous MMTV-R26 Met and human TNBC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Lamballe

Ahmad

Vinik

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity and resistance to treatment. Here, we report the generation of a unique mouse model (MMTV-R26 Met mice) in which a subtle increase in the expression levels of the wild-type MET receptor tyrosine kinase leads to spontaneous, exclusive TNBC formation, recapitulating TNBC heterogeneity. We further exploited the MMTV-R26 Met TNBC model by exploring signaling alterations through proteomics to search for TNBC vulnerability. We identified a new drug combination based on combinatorial targeting of WEE1 and BCL-XL that efficiently kills TNBC cells. Mechanistically, we show that BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS 33 RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, and depletion of oncogenic signals, resulting in mitotic catastrophe and apoptosis. Our findings suggest that combination therapy with BCL-XL and WEE1 inhibitors warrants further evaluation in clinical trials. Statement of significanceWe have developed a new TNBC mouse model that recapitulates resistance to chemotherapy and heterogeneity. We uncovered that combined inhibition of WEE1 and BCL-XL selectively kills mouse and human TNBC cells, and provided mechanistic insights underlying this combined targeting. We propose that BCL-XL inhibition exacerbates WEE1 requirement for TNBC survival. cancer subtypes, TNBC is characterized by the earliest age of onset, a higher prevalence in African-Americans, a high propensity for metastasis, and the worst prognosis in terms of relapse and survival rate (6,7). Over 80% of TNBC patients exhibit alterations in the TP53 locus (8), whereas a smaller fraction has mutations in genes controlling the PI3K pathway and homologous recombination including BRCA1/2 negative. A molecular feature of TNBC is the dependency of cancer cells on signals that are rarely mutated, a phenomenon defined as "non-oncogene addiction" (9). It is the case, for example, of components of the receptor tyrosine kinase (RTK) core pathway (7,10). Collectively, these traits are 4 among the leading cause of limited efficacy of current TNBC therapies. Radiation therapy and chemotherapy, applied before and after surgery, are the mainstay of treatment, although frequently associated with drug resistance and recurrent disease.Extensive efforts have been made to search for molecular targeted therapies effective for TNBC treatment. Although some targeted therapies approved for treatment of other cancer types have been proposed in TNBC, they rarely turned out to be clinically relevant (11). These limited responses are associated with the high heterogeneity of the disease and the lack of suitable immunocompetent preclinical models that recapitulate the molecular diversity of TNBC. Among potential targets for TNBC subsets are PARP1, androgen receptor (AR), vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR...

show abstract

“…The vulnerability of the mammary gland to a slight increase in MET levels resembles the susceptibility of the liver we reported in previous studies. [ 29–32 ] The vulnerability of the mammary gland and the liver is contrasted by a remarkable resilience of other tissues, in which a tumorigenic event requires additional genetic alterations, as reported for malignant peripheral nerve sheath tumors. [ 63 ] Whether such a mild MET perturbation in the mammary gland occurs in specific subgroups of women and/or physiological contexts and can increase susceptibility to tumor development remains an open issue.…”

Section: Discussionmentioning

confidence: 99%

“…[ 27–29 ] For example, at adulthood enhanced MET levels in the liver trigger spontaneous formation of hepatocellular carcinoma, recapitulating several features of human patients. [ 29–32 ] Here, we report the generation of a unique mouse model ( MMTV‐R26 Met mice) in which a subtle increase in the expression levels of the wild‐type MET RTK leads to spontaneous TNBC formation. The tumorigenic switch correlated with a critical threshold of MET expression, whereas aggressiveness was associated with high MET levels and discrete signaling reprogramming.…”

Section: Introductionmentioning

confidence: 99%

Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

et al. 2020

Self Cite

View full text Add to dashboard Cite

Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.

show abstract

Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography

Cited by 10 publications

References 55 publications

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Contact Info

Product

Resources

About