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International audience; Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth.Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L,which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed.Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L.Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.

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Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance 1,2. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy 2–4. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways 5–9. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5’-untranslated region. As a result, we found that sustained translation of IGF-1R mRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance.

5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse., Graphical Abstract Graphical Abstract5-FU integration in ribosomes contributes to cell plasticity through translational reprogramming.

Simple Summary Pancreatic cancer is an aggressive disease characterized by its invasiveness, rapid progression, and resistance to conventional therapy. There is a need to identify new molecules to improve current therapies. The aim of this study was to analyze how the pancreatic cancer cells react to the treatment with an inhibitor of nucleolin, N6L. To this end, we analyzed how the translation was affected in the cells during the treatment. We discovered that in response to N6L, a signaling pathway called the mTOR pathway was activated and was involved in the activation of translation of a subset of mRNA that could be involved in the resistance of the cells to the treatment. Indeed, we showed that the combined action of inhibitors of the mTOR pathway with N6L synergistically inhibited the cancer cells’ proliferation. We propose that this new combination of molecules could be a novel therapeutic option for pancreatic cancer. Abstract We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5′TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.

Apoptosis plays a role in cell homeostasis in both normal development and disease. Bcl-xL, a member of the Bcl-2 family of proteins, regulates the intrinsic mitochondrial pathway of apoptosis. It is overexpressed in several cancers. Bcl-xL has a dual subcellular localization and is found at the mitochondria as well as the endoplasmic reticulum (ER). However, the biological significance of its ER localization is unclear. In order to decipher the functional contributions of the mitochondrial and reticular pools of Bcl-xL, we generated genetically modified mice expressing exclusively Bcl-xL at the ER, referred to as ER-xL, or the mitochondria, referred to as Mt-xL. By performing cell death assays, we showed that ER-xL MEFs show increased vulnerability to apoptotic stimuli but are more resistant to ER stress. Furthermore, ER-xL MEFs demonstrated a reduced expression of the Unfolded Protein Response (UPR) markers upon ER stress and displayed reduced inositol trisphosphate receptor (IP3R)-mediated ER calcium release. Collectively, our data show that upon ER stress, Bcl-xL negatively regulates IP3R-mediated calcium flux from the ER, which prevents ER calcium depletion and maintains the UPR and subsequent cell death in check. This work reveals a moonlighting function of Bcl-xL at the ER, apart from its cliché regulation of apoptosis.

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has no effective treatment. Nucleolin targeting by the pseudopeptide N6L inhibits the tumor growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the pathways regulated by nucleolin and N6L in PDAC. We demonstrated that both interact with β-catenin, and that the Wnt/β-catenin pathway is activated in PDAC mouse models. Nucleolin inhibition decreases Wnt/β-catenin pathway activation in PDAC cells and tumors, and represents a new druggable pathway regulated by nucleolin. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.

International audience; G-rich oligonucleotide, AS1411, has been shown to interact with nucleolin and to inhibit cancer cell proliferation and tumor growth. This antiproliferative action is increased when AS1411 is conjugated to different types of nanoparticles. However, the molecular mechanisms are not known. In this work, we show in several cell lines that optimized AS1411-conjugated gold nanoparticles (GNS-AS1411) inhibit nucleolin expression at the RNA and protein levels. We observed an alteration of the nucleolar structure with a decrease of ribosomal RNA accumulation comparable to what is observed upon nucleolin knock down. However, the expression of genes involved in cell cycle and the cell cycle blockage by GNS-AS1411 are not regulated in the same way that in cells where nucleolin has been knocked down. These data suggest that the anti-proliferative activity of GNS-AS1411 is not the only consequence of nucleolin targeting and down-regulation.

Nucleolin is an RNA binding protein that is involved in many post-transcriptional regulation steps of messenger RNAs in addition to its nucleolar role in ribosomal RNA transcription and assembly in pre-ribosomes. Acetylated nucleolin was found to be associated with nuclear speckles and to co-localize with the splicing factor SC35. Previous nuclear pull down of nucleolin identified several splicing components and factors involved in RNA polymerase II transcription associated with nucleolin. In this report, we show that these splicing components are specifics of the pre-catalytic A and B spliceosomes, while proteins recruited in the Bact, C and P complexes are absent from the nucleolin interacting proteins. Furthermore, we show that acetylated nucleolin co-localized with P-SF3B1, a marker of co-transcriptional active spliceosomes. P-SF3B1 complexes can be pulled down with nucleolin specific antibodies. Interestingly, the alternative splicing of Fibronectin at the IIICS and EDB sites was affected by nucleolin depletion. These data are consistent with a model where nucleolin could be a factor bridging RNA polymerase II transcription and assembly of pre-catalytic spliceosome similarly to its function in the co-transcriptional maturation of pre-rRNA.

Discovered in 1973, nucleolin is one of the most abundant phosphoproteins of the nucleolus. The ability of nucleolin to be involved in many cellular processes is probably related to its structural organization and its capability to form many different interactions with other proteins. Many functions of nucleolin affect cellular processes involved in oncogenesis-for instance: in ribosome biogenesis; in DNA repair, remodeling, and genome stability; in cell division and cell survival; in chemokine and growth factor signaling pathways; in angiogenesis and lymphangiogenesis; in epithelial-mesenchymal transition; and in stemness. In this review, we will describe the different functions of nucleolin in oncogenesis through its interaction with other proteins.

International audience; Discovered in 1973, nucleolin is one of the most abundant phosphoproteins of the nucleolus. The ability of nucleolin to be involved in many cellular processes is probably related to its structural organization and its capability to form many different interactions with other proteins. Many functions of nucleolin affect cellular processes involved in oncogenesis-for instance: in ribosome biogenesis; in DNA repair, remodeling, and genome stability; in cell division and cell survival; in chemokine and growth factor signaling pathways; in angiogenesis and lymphangiogenesis; in epithelial-mesenchymal transition; and in stemness. In this review, we will describe the different functions of nucleolin in oncogenesis through its interaction with other proteins.

Somatostatin is an endogenous inhibitor of secretion and cell proliferation. These features render somatostatin a logical candidate for the management of neuroendocrine tumors that express somatostatin receptors. Synthetic somatostatin analogs (SSAs) have longer half-lives than somatostatin, but have similar activities, and are used for the treatment of these types of disorders. Interest has focused on novel multireceptor analogs with broader affinity to several of the five somatostatin receptors, thereby presenting putatively higher antitumor activities. Recent evidence indicates that SSAs cannot be considered mimics of native somatostatin in regulating signaling pathways downstream of receptors. Here we review this knowledge, discuss the concept of biased agonism, and highlight what considerations need to be taken into account for the optimal clinical use of SSAs. Refereed/Peer-reviewed

Context: Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR). Evidence Acquisition: The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy. Evidence Synthesis: The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which ...

Comment inSomatostatin receptor subtype 2 as pancreatic tumorigenesis suppressor: identification of a new targetable signaling node. [Gastroenterology. 2015]; International audience; BACKGROUND & AIMS:The KRAS gene is mutated in most pancreatic ductal adenocarcinomas (PDAC). Expression of this KRAS oncoprotein in mice is sufficient to initiate carcinogenesis but not progression to cancer. Activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is required for KRAS for induction and maintenance of PDAC in mice. The somatostatin receptor subtype 2 (sst2) inhibits PI3K, but sst2 expression is lost during the development of human PDAC. We investigated the effects of sst2 loss during KRAS-induced PDAC development in mice.METHODS:We analyzed tumor growth in mice that expressed the oncogenic form of KRAS (KRAS(G12D)) in pancreatic precursor cells, as well as sst2+/- and sst2-/-, and in crossed KRAS(G12D);sst2+/- and KRAS(G12D);sst2-/- mice. Pancreatic tissues and acini were collected and assessed by histologic, immunoblot, immunohistochemical, and reverse-transcription polymerase chain reaction analyses. We also compared protein levels in paraffin-embedded PDAC samples from patients vs heathy pancreatic tissues from individuals without pancreatic cancer.RESULTS:In sst2+/- mice, PI3K was activated and signaled via AKT (PKB; protein kinase B); when these mice were crossed with KRAS(G12D) mice, premalignant lesions, tumors, and lymph node metastases developed more rapidly than in KRAS(G12D) mice. In crossed KRAS(G12D);sst2+/- mice, activation of PI3K signaling via AKT resulted in activation of nuclear factor-κB (NF-κB), which increased KRAS activity and its downstream pathways, promoting initiation and progression of neoplastic lesions. We found this activation loop to be mediated by PI3K-induced production of the chemokine CXCL16. Administration of a CXCL16-neutralizing antibody to KRAS(G12D) mice reduced activation of PI3K signaling to AKT and NF-κB, blocking carcinogenesis. Levels of CXCL16 and its receptor CXCR6 were significantly higher in PDAC tissues and surrounding acini than in healthy pancreatic tissues from mice or human beings. In addition, expression of sst2 was progressively lost, involving increased PI3K activity, in mouse lesions that expressed KRAS(G12D) and progressed to PDAC.CONCLUSIONS:Based on analyses of mice, loss of sst2 from pancreatic tissues activates PI3K signaling via AKT, leading to activation of NF-κB, amplification of oncogenic KRAS signaling, increased expression of CXCL16, and pancreatic tumor formation. CXCL16 might be a therapeutic target for PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of α-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential.

Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. First, presence of HDs has been explored in normal and cancer pancreatic cells and patient samples by transmission electron and confocal microscopy. Mature type-1 HDs, composed of the integrin α6β4 and plectin, as well as of the bullous pemphigoid antigens BP180 and BP230, are known to be present in stratified epithelia, whereas simple epithelia rather contain immature type-2 HDs composed of the integrin α6β4 and plectin only. We here describe for the first time the presence of mature type-1 HDs in human pancreatic ducts, a simple epithelium. Importantly, these structures are disrupted in pancreatic cancer cells, in association with the proteolytic cleavage of BP180 into a non-functional BP120 form (no adhesive properties to the basement membrane). To investigate the role and molecular mechanisms of HD dynamic during pancreatic carcinogenesis, unique cancer cell models where HD assembly can be pharmacologically manipulated by activation of the somatostatin/sst2 receptor signaling have been used. Using these in vitro as well as in vivo models of pancreatic cancer cells xenografted into nude mice or chick chorioallantoic membrane, we provide molecular evidences that HD breakdown relies on the activation of the master oncogenic phosphoinositide 3-kinase (PI3K) pathway in cancer cells: high PI3K activity induces the expression of the matrix-metalloproteinase MMP9, subsequently promoting the proteolytic cleavage of the hemidesmosomal BP180 protein. Using a siRNA strategy targeting BP180, we demonstrate that HD disruption is a prerequisite for integrin α6β4 delocalization from HD (at the cell basal layer) to the cell leading edges where it is phosphorylated and paradoxically promotes cell migration and invasion by inducing the expression of the pro-migratory S100A4 protein. S100A4 then stimulates MMP-9 expression, thereby inducing a positive feedback loop sustaining BP180 cleavage and HD disruption. Pharmacological inactivation (activation of the somatostatin/sst2 signaling or specific PI3K inhibitor) of this PI3K-MMP9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion, whereas rescuing S100A4 or MMP9 expression in a PI3K-inhibited context restores HD breakdown and cell invasion. Our results therefore demonstrate that HDs are critical anchoring structures for the pancreatic ductal epithelium whose PI3K-dependent disruption during carcinogenesis promotes cell migration and invasion. By inhibiting PI3K and the subsequent MMP9-S100A4-MMP9 vicious cycle, activation of sst2 forces HD reassembly and inhibits pancreatic cancer cell migration and invasion. This is consistent with our data demonstrating that sst2 deficiency accelerates pancreatic carcinogenesis induced by the oncogenic Kras G12D allelic mutation in the transgenic mouse PDX-1-Cre;LSL-KRAS G12D ;sst2 +/- model. Citation Format: Severine Laval, Mounira Chalabi, Hanane Laklai, Marjorie Fanjul, Hubert Lulka, Talal Al Saati, Marie-Bernadette Delisle, Stephane Pyronnet, Corinne Bousquet. Critical role of hemidesmosome breakdown for human pancreatic cancer cell migration and invasion. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B60.

Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR).The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy.The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy.The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors.

Pancreatic ductal adenocarcinoma (PDAC) is extremely rich in stroma. By secreting tremendous amounts of soluble and un-soluble proteins, stromal cancer-associated fibroblasts (CAFs) can induce tumor chemoresistance by activating survival signals in cancer cells and preventing drug delivery through increased fibrosis. Our results demonstrate that chemoresistance triggered by the CAF secretome is strongly reduced upon inhibition of CAF protein synthesis. This is achieved by impinging upon the PI3K/mTOR/4E-BP1 pathway that we found highly activated in primary cultures of alpha-SMA-positive CAFs isolated from human PDAC. CAFs, but not normal pancreatic fibroblasts, express primarily the sstr1 somatostatin receptor subtype whose activation by the somatostatin analogue SOM230 (Pasireotide) strongly inhibits the PI3K/mTOR/4E-BP1 pathway and the resulting synthesis of secreted proteins including IL-6 and collagen-I. As a consequence, the growth and chemoresistance of pancreatic tumors provided by co-injection of CAFs in nude mice are overcome when chemotherapy (such as gemcitabine) is combined to pasireotide treatment. While gemcitabine or pasireotide alone have marginal effects, the combined treatment markedly decreases fibrosis and strongly enhances cancer cell apoptosis due to increased cell sensitivity to gemcitabine. We propose that selective inhibition of CAF protein synthesis and secretion with sstr1-directed pharmacological compounds represents an anti-stromal targeted therapy with a promising potential in chemosensitization. Citation Format: Camille Duluc, Siham Moatassim, Mounira Chalabi, Aurélie Perraud, Yvan Martineau, Florence Breibach, Marie-Bernadette Delisle, Muriel Mathonnet, Herbert A. Schmid, Stéphane Pyronnet, Corinne Bousquet. Pasireotide reduces chemoresistance in pancreatic tumor cells by inhibiting the synthesis and secretion of growth factors from tumor associated fibroblasts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 402. doi:10.1158/1538-7445.AM2015-402

While a number of mouse models have been made to recapituate FAP, they fall short of truly mimicking the hallmarks of the human disorder. In lineage tracing studies (Powell et al., Cell, March 2012), we found that Leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1), a pan-ErbB inhibitor, marks a population of stem cells at the base of small intestinal and colonic crypts. In our current study, we combined our Lrig1-CreERT2/+ mice with Apcflox/+ mice and eliminated one copy of Apc with tamoxifen injection. Over a period of 50-100 days, the mice developmultiple distal colonic tumors as monitored by colonoscopy, as well as by novel non-invasive imaging (tumor formation measured by TSPO ligand binding monitored via PET). These mice also exhibit periampullary and duodenal tumors, as well as gastric lesions, thus mimicking additional features of FAP. Of interest, Lrig1-CreERT2/ +;Apcflox/+ mice also have CHRPE-like lesions in their retinal pigment epithelium. Finally, when induced Lrig1-CreERT2/+;Apcflox/flox mice were treated (i.p.) with a novel Wnt inhibitor, VU-WS113, cytosolic β-catenin was markedly reduced and TSPO uptake was also dramatically decreased, providing in vivo evidence that VU-WS113 may be an effective therapy for Wnt-driven tumors. We are in the process of comparing the transcriptional profiles of Lrig1-CreERT2/+;Apcflox/+ colonic tumors and human FAP tumors to understand their similarities and differences at a molecular level. In summary, in addition to recapitulating a number of features of human FAP the most important of which is distal, colonic tumors our results suggest this model represents a tractable system to test the efficacy of innovative therapeutic interventions whose efficacy can be monitored over time by colonoscopy and non-invasive imaging modalities.