Autophagy and lysosomal dysfunction in diabetes and its complications.

Autophagy is critical for energy homeostasis and the function of organelles such as endoplasmic reticulum (ER) and mitochondria. Dysregulated autophagy due to aging, environmental factors, or genetic predisposition can be an underlying cause of not only diabetes through ß-cell dysfunction and metabolic inflammation, but also diabetic complications such as diabetic kidney diseases (DKDs). Dysfunction of lysosomes, effector organelles of autophagic degradation, due to metabolic stress or nutrients/metabolites accumulating in metabolic diseases is also emerging as a cause or aggravating element in diabetes and its complications. Here, we discuss the etiological role of dysregulated autophagy and lysosomal dysfunction in diabetes and a potential role of autophagy or lysosomal modulation as a new avenue for treatment of diabetes and its complications.

Perfluorooctanesulfonic acid exposure leads to downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 2 expression and upregulation of markers associated with intestinal carcinogenesis in mouse intestinal tissues.

Perfluorooctanesulfonic acid (PFOS) is a widely recognized environment pollutant known for its high bioaccumulation potential and a long elimination half-life. Several studies have shown that PFOS can alter multiple biological pathways and negatively affect human health. Considering the direct exposure to the gastrointestinal (GI) tract to environmental pollutants, PFOS can potentially disrupt intestinal homeostasis. However, there is limited knowledge about the effect of PFOS exposure on normal intestinal tissues, and its contribution to GI-associated diseases remains to be determined. In this study, we examined the effect of PFOS exposure on the gene expression profile of intestinal tissues of C57BL/6 mice using RNAseq analysis. We found that PFOS exposure in drinking water significantly downregulates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme, in intestinal tissues of mice. We found that diets containing the soluble fibers inulin and pectin, which are known to be protective against PFOS exposure, were ineffective in reversing the downregulation of HMGCS2 expression in vivo. Analysis of intestinal tissues also demonstrated that PFOS exposure leads to upregulation of proteins implicated in colorectal carcinogenesis, including ß-catenin, c-MYC, mTOR and FASN. Consistent with the in vivo results, PFOS exposure leads to downregulation of HMGCS2 in mouse and human normal intestinal organoids in vitro. Furthermore, we show that shRNA-mediated knockdown of HMGCS2 in a human normal intestinal cell line resulted in increased cell proliferation and upregulation of key proliferation-associated proteins such as cyclin D, survivin, ERK1/2 and AKT, along with an increase in lipid accumulation. In summary, our results suggest that PFOS exposure may contribute to pathological changes in normal intestinal cells via downregulation of HMGCS2 expression and upregulation of pro-carcinogenic signaling pathways that may increase the risk of colorectal cancer development.

Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development.

Peroxiredoxin IV (Prx4), a typical two-cysteine-containing member of the peroxidase family, functions as an antioxidant to maintain cellular redox homeostasis through the reduction of reactive oxygen species (ROS) via cycles of oxidation-reduction reactions. Under oxidative stress, all Prxs including Prx4 are inactivated as their catalytic cysteines undergo hyperoxidation, and hyperoxidized two-cysteine Prxs can be exclusively repaired and revitalized through the reduction cycle catalyzed by sulfiredoxin (Srx). Previously, we showed that Prx4 is a preferred substrate of Srx, and knockout of Srx in mice leads to resistance to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis. To further understand the significance of the Srx/Prx4 axis in colorectal cancer development, Prx4-/- mice were established and subjected to standard AOM/DSS protocol. Compared with wildtype littermates, mice with Prx4-/- genotype had significantly fewer and smaller tumors. Histopathological analysis revealed that loss of Prx4 leads to increased cell death through lipid peroxidation and lower infiltration of inflammatory cells in the knockout tumors compared to wildtype. Treatment with DSS alone also showed decreased infiltration of macrophages and lymphocytes in the colon of knockout mice, suggesting a role for Prx4 in inflammatory response. In addition, loss of Prx4 caused alterations in plasma cytokines and chemokines after DSS and AOM/DSS treatments. These findings suggest that loss of Prx4 protects mice from AOM/DSS-induced colon tumorigenesis. Thus, targeting Prx4 may provide novel strategies for colon cancer prevention and treatment.

POU2AF3-rearranged sarcomas: A novel tumor defined by fusions of EWSR1 or FUS to a gene formerly designated COLCA2.

Gene fusions involving EWSR1 or FUS as the 5' partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1/FUS along with similar breakpoints in POU2AF3 that encompassed a 3' portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3-rearranged sarcomas with aggressive, malignant behavior.

Associations between breastfeeding intention, breastfeeding practices and post-natal depression during the COVID-19 pandemic: A multi-country cross-sectional study.

Associations between breastfeeding intention, duration and post-natal depression (PND) have been shown in pre-COVID-19 studies. However, studies during COVID-19 have not examined the associations between breastfeeding intention, breastfeeding practices, and PND in an international sample of post-natal women, taking into consideration COVID-19 related factors. This is the first study to address this gap as both PND and breastfeeding may be affected by COVID-19, and have important long-term effects on women's and infant's health. A cross-sectional internet-based survey was conducted with 3253 post-natal women from five countries: Brazil, South Korea, Taiwan, Thailand, and the United Kingdom from July to November 2021. The results showed that women who intended to breastfeed during pregnancy had lower odds of having PND than women who did not intend to. Women who had no breastfeeding intention but actually breastfed had greater odds (AOR 1.75) of having PND than women who intended to breastfeed and actually breastfed. While there was no statistical significance in expressed breast milk feeding in multivariable logistic regression models, women who had shorter duration of breastfeeding directly on breast than they planned had greater odds (AOR 1.58) of having PND than those who breastfed longer than they planned even after adjusting for covariates including COVID-19-related variables. These findings suggested the importance of working with women on their breastfeeding intention. Tailored support is required to ensure women's breastfeeding needs are met and at the same time care for maternal mental health during and beyond the pandemic.

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression.

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36-MMP28 axis may be an effective therapeutic strategy for CRC metastasis.

Potent Synergistic Effect on C-Myc-Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor.

Developing effective treatments for colorectal cancers through combinations of small-molecule approaches and immunotherapies present intriguing possibilities for managing these otherwise intractable cancers. During a broad-based, screening effort against multiple colorectal cancer cell lines, we identified indole-substituted quinolines (ISQ), such as N7,N7 -dimethyl-3-(1-methyl-1H-indol-3-yl)quinoline-2,7-diamine (ISQ-1), as potent in vitro inhibitors of several cancer cell lines. We found that ISQ-1 inhibited Wnt signaling, a main driver in the pathway governing colorectal cancer development, and ISQ-1 also activated adenosine monophosphate kinase (AMPK), a cellular energy-homeostasis master regulator. We explored the effect of ISQs on cell metabolism. Seahorse assays measuring oxygen consumption rate (OCR) indicated that ISQ-1 inhibited complex I (i.e., NADH ubiquinone oxidoreductase) in the mitochondrial, electron transport chain (ETC). In addition, ISQ-1 treatment showed remarkable synergistic depletion of oncogenic c-Myc protein level in vitro and induced strong tumor remission in vivo when administered together with BI2536, a polo-like kinase-1 (Plk1) inhibitor. These studies point toward the potential value of dual drug therapies targeting the ETC and Plk-1 for the treatment of c-Myc-driven cancers.

Ketogenesis alleviates TNFα-induced apoptosis and inflammatory responses in intestinal cells.

The disturbance of strictly regulated self-regeneration in mammalian intestinal epithelium is associated with various intestinal disorders, particularly inflammatory bowel diseases (IBDs). TNFα, which plays a critical role in the pathogenesis of IBDs, has been reported to inhibit production of ketone bodies such as ß-hydroxybutyrate (ßHB). However, the role of ketogenesis in the TNFα-mediated pathological process is not entirely known. Here, we showed the regulation and role of HMGCS2, the rate-limiting enzyme of ketogenesis, in TNFα-induced apoptotic and inflammatory responses in intestinal epithelial cells. Treatment with TNFα dose-dependently decreased protein and mRNA expression of HMGCS2 and its product, ßHB production in human colon cancer cell lines HT29 and Caco2 cells and mouse small intestinal organoids. Moreover, the repressed level of HMGCS2 protein was found in intestinal epithelium of IBD patients with Crohn's disease and ulcerative colitis as compared with normal tissues. Furthermore, knockdown of HMGCS2 enhanced and in contrast, HMGCS2 overexpression attenuated, the TNFα-induced apoptosis and expression of pro-inflammatory chemokines (CXCL1-3) in HT29, Caco2 cells and DLD1 cells, respectively. Treatment with ßHB or rosiglitazone, an agonist of PPARγ, which increases ketogenesis, attenuated TNFα-induced apoptosis in the intestinal epithelial cells. Finally, HMGCS2 knockdown enhanced TNFα-induced reactive oxygen species (ROS) generation. In addition, hydrogen peroxide, the major ROS contributing to intestine injury, decreased HMGCS2 expression and ßHB production in the intestinal cells and mouse organoids. Our findings demonstrate that increased ketogenesis attenuates TNFα-induced apoptosis and inflammation in intestinal cells, suggesting a protective role for ketogenesis in TNFα-induced intestinal pathologies.

Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. We previously showed that TSP1 has an important role in obesity-associated metabolic complications, including inflammation, insulin resistance, cardiovascular, and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD or NASH) remains largely unknown; thus, we aimed to determine its role. METHODS: High-fat diet or AMLN (amylin liver NASH) diet-induced obese and insulin-resistant NAFLD/NASH mouse models were utilised, in addition to tissue-specific Tsp1-knockout mice, to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. RESULTS: Liver TSP1 levels were increased in experimental obese and insulin-resistant NAFLD/NASH mouse models as well as in obese patients with NASH. Moreover, TSP1 deletion in adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection was independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed Smpdl3b expression in liver, which amplified liver proinflammatory signalling (Toll-like receptor 4 signal pathway) and promoted NAFLD progression. CONCLUSIONS: Macrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and could serve as a therapeutic target for this disease. LAY SUMMARY: Obesity-associated non-alcoholic fatty liver disease is a most common chronic liver disease in the Western world and can progress to liver cirrhosis and cancer. No treatment is currently available for this disease. The present study reveals an important factor (macrophage-derived TSP1) that drives macrophage activation and non-alcoholic fatty liver disease development and progression and that could serve as a therapeutic target for non-alcoholic fatty liver disease/steatohepatitis.

Inhibition of Fatty Acid Synthase Upregulates Expression of CD36 to Sustain Proliferation of Colorectal Cancer Cells.

Fatty acid synthase, a key enzyme of de novo lipogenesis, is an attractive therapeutic target in cancer. The novel fatty acid synthase inhibitor, TVB-3664, shows anti-cancer activity in multiple cancers including colorectal cancer; however, it is unclear whether uptake of exogeneous fatty acids can compensate for the effect of fatty acid synthase inhibition. This study demonstrates that inhibition of fatty acid synthase selectively upregulates fatty acid translocase (CD36), a fatty acid transporter, in multiple colorectal cancer models including colorectal cancer cells with shRNA mediated knockdown of fatty acid synthase and genetically modified mouse tissues with heterozygous and homozygous deletion of fatty acid synthase. Furthermore, human colorectal cancer tissues treated with TVB-3664 show a significant and selective upregulation of CD36 mRNA. shRNA-mediated knockdown of CD36 and inhibition of CD36 via sulfosuccinimidyl oleate, a chemical inhibitor of CD36, decreased cell proliferation in vitro and reduced tumor growth in subcutaneous xenograft models. Isogenic cell populations established from patient derived xenografts and expressing high levels of CD36 show a significantly increased ability to grow tumors in vivo. The tumor-promoting effect of CD36 is associated with an increase in the levels of pAkt and survivin. Importantly, combinatorial treatment of primary and established colorectal cancer cells with TVB-3664 and sulfosuccinimidyl oleate shows a synergistic effect on cell proliferation. In summary, our study demonstrates that upregulation of CD36 expression is a potential compensatory mechanism for fatty acid synthase inhibition and that inhibition of CD36 can improve the efficacy of fatty acid synthase-targeted therapy.

Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression.

Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC.

p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment in prostate cancer.

Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer, including prostate cancer (PCa), is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers, including PCa. This suggests that cutting off the secretion or expression of PD-L1 might improve the response rate of PD-L1 blockade therapy in PCa treatment. Here we report that p300/CBP inhibition by a small molecule p300/CBP inhibitor dramatically enhanced the efficacy of PD-L1 blockade treatment in a syngeneic model of PCa by blocking both the intrinsic and IFN-γ-induced PD-L1 expression. Mechanistically, p300/CBP could be recruited to the promoter of CD274 (encoding PD-L1) by the transcription factor IRF-1, which induced the acetylation of Histone H3 at CD274 promoter followed by the transcription of CD274. A485, a p300/CBP inhibitor, abrogated this process and cut off the secretion of exosomal PD-L1 by blocking the transcription of CD274, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. This finding reports a new mechanism of how cancer cells regulate PD-L1 expression through epigenetic factors and provides a novel therapeutic approach to enhance the efficacy of immune checkpoint inhibitors treatment.

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation.

BACKGROUND AND AIMS: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. METHODS: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. RESULTS: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/ß-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. CONCLUSION: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-ß-catenin signaling and is important for maintenance of IEC proliferation and differentiation.

In vivo ß-catenin attenuation by the integrin α5-targeting nano-delivery strategy suppresses triple negative breast cancer stemness and metastasis.

Cancer stem cells (CSCs) play pivotal roles in cancer metastasis, and strategies targeting cancer stemness may greatly reduce cancer metastasis and improve patients' survival. The canonical Wnt/ß-catenin pathway plays critical roles in CSC generation and maintenance as well as in normal stem cells. Non-specifically suppressing the Wnt/ß-catenin pathway for cancer therapy could be deleterious to normal cells. To achieve specific ß-catenin attenuation in cancer cells, we report an integrin α5 (ITGA5)-targeting nanoparticle for treating metastatic triple negative breast cancer (TNBC). We found that ITGA5 is highly expressed in strongly migratory and invasive TNBC cells as well as their lung metastatic foci, which rationalizes active-targeted drug delivery to TNBC cells via ITGA5 ligands such as a commercialized ligand-RGD motif (Arg-Gly-Asp). We modified lipid-polymer hybrid (LPH) nanoparticle for TNBC-targeted delivery of diacidic norcantharidin (NCTD), a potent anti-cancer compound but with short half-life. Notably, in vivo imaging analysis showed that RGD-decorated LPH (RGD-LPH) accumulated more significantly and remained much longer than LPH in nude mouse orthotopic mammary TNBC tumor and lung metastatic tumor, which implicated the feasibility of ITGA5-targeting strategy for treating metastatic TNBC. Moreover, systemic administration of NCTD-loaded RGD-LPH (RGD-LPH-NCTD) reduced nude mouse orthotopic mammary TNBC tumor growth and metastasis more effectively than free NCTD and LPH-NCTD via down-regulating ß-catenin. These findings suggest that ITGA5-targeting nanoparticles may provide a facil and unique strategy of specially attenuating ß-catenin in vivo for treating metastatic TNBC.

De Novo Fatty Acid Synthesis-Driven Sphingolipid Metabolism Promotes Metastatic Potential of Colorectal Cancer.

Metastasis is the most common cause of death in colorectal cancer patients. Fatty acid synthase (FASN) and sphingosine kinase-1 and -2 (SPHK1 and 2) are overexpressed in many cancers, including colorectal cancer. However, the contribution of FASN-mediated upregulation of sphingolipid metabolism to colorectal cancer metastasis and the potential of these pathways as targets for therapeutic intervention remain unknown. This study determined that sphingosine kinases (SPHK) are overexpressed in colorectal cancer as compared with normal mucosa. FASN expression significantly correlated with SPHK2 expression in data sets from The Cancer Genome Atlas (TCGA) and a colorectal cancer tumor microarray. FASN, SPHK1, and SPHK2 colocalized within invadopodia of primary colorectal cancer cells. Moreover, FASN inhibition decreased SPHK2 expression and the levels of dihydrosphingosine 1-phosphate (DH-S1P) and sphingosine 1-phosphate (S1P) in colorectal cancer cells and tumor tissues. Inhibition of FASN using TVB-3664 and sphingolipid metabolism using FTY-720 significantly inhibited the ability of primary colorectal cancer cells to proliferate, migrate, form focal adhesions, and degrade gelatin. Inhibition of the FASN/SPHK/S1P axis was accompanied by decreased activation of p-MET, p-FAK, and p-PAX. S1P treatment rescued FASN-mediated inhibition of these proteins, suggesting that FASN promotes metastatic properties of colorectal cancer cells, in part, through an increased sphingolipid metabolism. These data demonstrate that upregulation of the FASN/SPHK/S1P axis promotes colorectal cancer progression by enhancing proliferation, adhesion, and migration. IMPLICATIONS: This study provides a strong rationale for further investigation of the interconnection of de novo lipogenesis and sphingolipid metabolism that could potentially lead to the identification of new therapeutic targets and strategies for colorectal cancer.

Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer.

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs. In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC.