bims-instec 2024-05-19 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2024‒05‒19
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.
Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth.
The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells.
TGFβ-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.
Molecular mechanism of MLCK1 inducing 5-Fu resistance in colorectal cancer cells through activation of TNFR2/NF-κB pathway.
Rethinking colorectal cancer prognosis: beyond microsatellite status.
Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy.
Hypoxia-induced NOS1 as a therapeutic target in hypercholesterolemia-related colorectal cancer.
NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Regeneration.
Hepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture.
HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis.
Overexpression of Fatty Acid Synthase Upregulates Glutamine-Fructose-6-Phosphate Transaminase 1 and O-Linked N-Acetylglucosamine Transferase to Increase O-GlcNAc Protein Glycosylation and Promote Colorectal Cancer Growth.
Decoding the interplay between genetic and non-genetic drivers of metastasis.

Cell Stem Cell. 2024 May 07. pii: S1934-5909(24)00142-5. [Epub ahead of print]

Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.

Pratik N P Singh, Wei Gu, Shariq Madha, Allen W Lynch, Paloma Cejas, Ruiyang He, Swarnabh Bhattacharya, Miguel Muñoz Gomez, Matthew G Oser, Myles Brown, Henry W Long, Clifford A Meyer, Qiao Zhou, Ramesh A Shivdasani.

  Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and cis-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct ASCL1+ and HES6hi cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind cis-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.

Keywords:  chromatin dynamics; determination of terminal cell fates; hormone producing cells; human enteroendocrine cells; intestinal stem cells; transcription factor oscillation

DOI:  https://doi.org/10.1016/j.stem.2024.04.015
Nat Commun. 2024 May 13. 15(1): 4034

Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth.

Delilah Hendriks, Benedetta Artegiani, Thanasis Margaritis, Iris Zoutendijk, Susana Chuva de Sousa Lopes, Hans Clevers.

Mechanisms underlying human hepatocyte growth in development and regeneration are incompletely understood. In vitro, human fetal hepatocytes (FH) can be robustly grown as organoids, while adult primary human hepatocyte (PHH) organoids remain difficult to expand, suggesting different growth requirements between fetal and adult hepatocytes. Here, we characterize hepatocyte organoid outgrowth using temporal transcriptomic and phenotypic approaches. FHs initiate reciprocal transcriptional programs involving increased proliferation and repressed lipid metabolism upon initiation of organoid growth. We exploit these insights to design maturation conditions for FH organoids, resulting in acquisition of mature hepatocyte morphological traits and increased expression of functional markers. During PHH organoid outgrowth in the same culture condition as for FHs, the adult transcriptomes initially mimic the fetal transcriptomic signatures, but PHHs rapidly acquire disbalanced proliferation-lipid metabolism dynamics, resulting in steatosis and halted organoid growth. IL6 supplementation, as emerged from the fetal dataset, and simultaneous activation of the metabolic regulator FXR, prevents steatosis and promotes PHH proliferation, resulting in improved expansion of the derived organoids. Single-cell RNA sequencing analyses reveal preservation of their fetal and adult hepatocyte identities in the respective organoid cultures. Our findings uncover mitogen requirements and metabolic differences determining proliferation of hepatocytes changing from development to adulthood.

DOI: https://doi.org/10.1038/s41467-024-48550-4
BMC Cancer. 2024 May 14. 24(1): 587

The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells.

Věra Slaninová, Lisa Heron-Milhavet, Mathilde Robin, Laura Jeanson, Adam Aissanou, Diala Kantar, Diego Tosi, Laurent Bréhélin, Céline Gongora, Alexandre Djiane.

  YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Keywords:  Colon cancer; Hippo signaling; Oxaliplatin; TAZ; p53

DOI:  https://doi.org/10.1186/s12885-024-12316-4
Int J Mol Sci. 2024 Apr 24. pii: 4626. [Epub ahead of print]25(9):

TGFβ-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Hideaki Tsumuraya, Hirokazu Okayama, Masanori Katagata, Akira Matsuishi, Satoshi Fukai, Misato Ito, Wataru Sakamoto, Motonobu Saito, Tomoyuki Momma, Shotaro Nakajima, Kosaku Mimura, Koji Kono.

  Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Keywords:  BRAF mutation; TGFβ; colorectal cancer; serrated lesion; serrated pathway

DOI:  https://doi.org/10.3390/ijms25094626
Discov Oncol. 2024 May 12. 15(1): 159

Molecular mechanism of MLCK1 inducing 5-Fu resistance in colorectal cancer cells through activation of TNFR2/NF-κB pathway.

Huifen Tang, Hui Zhou, Liang Zhang, Tingting Tang, Ning Li.

  BACKGROUND AND AIMS: Chemotherapy resistance in colorectal cancer have been faced with significant challenges in recent years. Particular interest is directed to tumor microenvironment function. Recent work has, identified a small molecule named Divertin that prevents myosin light chain kinase 1(MLCK1) recruitment to the perijunctional actomyosin ring(PAMR), restores barrier function after tumor necrosis factor(TNF)-induced barrier loss and prevents disease progression in experimental inflammatory bowel disease. Studies have shown that MLCK is a potential target for affecting intestinal barrier function, as well as for tumor therapy. However, the relative contributions of MLCK expression and chemotherapy resistance in colorectal cancers have not been defined.METHODS: Statistical analysis of MYLK gene expression differences in colorectal cancer patients and normal population and prognosis results from The Cancer Genome Atlas(TCGA) data. Cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. Determine the role of MLCK1 in inducing 5-Fluorouracil(5-Fu) resistance in colorectal cancer cells was detected by overexpression of MLCK1 and knock-down expression of MLCK1.
RESULTS: MLCK1 is expressed at different levels in different colorectal cancer cells, high MLCK1 expressing cell lines are less sensitive to 5-Fu, and low MLCK1 expressing cell lines are more sensitive to 5-Fu. MLCK1 high expression enhances resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway.
CONCLUSIONS: MLCK1 high expression can enhance resistance to 5-Fu in colorectal cancer cells and the sensitivity to 5-Fu was increased after knocking down the expression of MLCK1, that might be closely correlated to TNFR2/NF-κB pathway, which will provide a new method for the treatment of colorectal cancer patients who are resistant to 5-Fu chemotherapy.

Keywords:  5-Fluorouracil (5-Fu); Chemotherapy resistance; Colorectal cancer (CRC); Myosin light chain kinase 1(MLCK1); TNFR2/NF-κB pathway

DOI:  https://doi.org/10.1007/s12672-024-01019-8
Lancet Gastroenterol Hepatol. 2024 May 08. pii: S2468-1253(24)00129-8. [Epub ahead of print]

Rethinking colorectal cancer prognosis: beyond microsatellite status.

Elisabetta Fenocchio.

DOI: https://doi.org/10.1016/S2468-1253(24)00129-8
Molecules. 2024 May 02. pii: 2110. [Epub ahead of print]29(9):

Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy.

Domiziana Masci, Michela Puxeddu, Romano Silvestri, Giuseppe La Regina.

  Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.

Keywords:  Warburg effect; cancer; colorectal cancer; glutaminolysis; lactate dehydrogenase; lipid metabolism; metabolism

DOI:  https://doi.org/10.3390/molecules29092110
Cancer Metab. 2024 May 17. 12(1): 14

Hypoxia-induced NOS1 as a therapeutic target in hypercholesterolemia-related colorectal cancer.

Weiqing Qiu, Li Zhao, Hua Liu, Ping Xu, Changlin Qian.

  BACKGROUND: It is well established that hypercholesterolemia increases the risk of atherosclerosis, especially because it reduces the availability of nitric oxide (NO). However, the relationship between hypercholesterolemia and NO in regulating colorectal cancer development and progression remains unknown.METHODS: We conducted bioinformatics analysis, qRT-PCR, ChIP-qPCR assays, luciferase report assays, clonogenic survival assays, and multiple mouse models to investigate the function and mechanism of hypercholesterolemia in regulating NO signaling. Additionally, NOS inhibitors were used to evaluate the potential of therapeutic strategy in anti-tumor response.
RESULTS: Here, we show that oxidized low-density lipoprotein (oxLDL) cholesterol and its receptor LOX-1 are essential for hypercholesterolemia-induced colorectal tumorigenesis. Mechanically, the oxLDL promotes the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NO synthase (NOS) especially NOS1 expression in colorectal cancer (CRC) cells. More importantly, our results suggested that selective inhibition of NOS1 with its specific inhibitor Nω-Propyl-L-arginine is a suitable therapeutic strategy for hypercholesterolemia-related CRC with both efficacy and toxicity reduction.
CONCLUSIONS: Our findings established that hypercholesterolemia induces the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NOS1 expression in CRC cells, and the clinically applicable NOS1 inhibitor Nω-Propyl-L-arginine represents an effective therapeutic strategy for hypercholesterolemia-related CRC.

Keywords:  Colorectal cancer; Hypercholesterolemia; Hypoxia; Nitric oxide synthase; Oxidized low-density lipoprotein

DOI:  https://doi.org/10.1186/s40170-024-00338-2
Cell Mol Gastroenterol Hepatol. 2024 May 13. pii: S2352-345X(24)00110-3. [Epub ahead of print]

NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Regeneration.

Holly A Morrison, Kristin Eden, Brie Trusiano, Daniel E Rothschild, Yufeng Qin, Paul A Wade, Audrey J Rowe, Christina Mounzer, Morgan C Stephens, Katherine M Hanson, Stephan L Brown, Eda K Holl, Irving C Allen.

  BACKGROUND & AIMS: Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/differentiation via noncanonical NF-κB signaling that is unique from canonical NF-κB signaling.METHODS: Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis was initiated in whole-body NIK knockout mice (Nik-/-)and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium (AOM/DSS).
RESULTS: Human transcriptomic data revealed dysregulated noncanonical NF-κB signaling. In vitro studies evaluating Nik-/- crypts and organoids derived from mature, nondividing CECs and colonic stem cells (CSCs) exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik-/- cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik-/- mice exhibited more severe colitis with DSS administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (NikΔCEC). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (NikΔMYE). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelAΔMYE) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelAΔCEC).
CONCLUSIONS: Dysregulated noncanonical NF-κB signaling is associated with the development of colorectal cancer in a tissue dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.

Keywords:  colitis-associated tumorigenesis; differentiation; epithelial cells; organoids

DOI:  https://doi.org/10.1016/j.jcmgh.2024.05.004
Nat Commun. 2024 May 15. 15(1): 3940

Hepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture.

Shizuka Miura, Kenichi Horisawa, Tokuko Iwamori, Satoshi Tsujino, Kazuya Inoue, Satsuki Karasawa, Junpei Yamamoto, Yasuyuki Ohkawa, Sayaka Sekiya, Atsushi Suzuki.

Hepatocytes play important roles in the liver, but in culture, they immediately lose function and dedifferentiate into progenitor-like cells. Although this unique feature is well-known, the dynamics and mechanisms of hepatocyte dedifferentiation and the differentiation potential of dedifferentiated hepatocytes (dediHeps) require further investigation. Here, we employ a culture system specifically established for hepatic progenitor cells to study hepatocyte dedifferentiation. We found that hepatocytes dedifferentiate with a hybrid epithelial/mesenchymal phenotype, which is required for the induction and maintenance of dediHeps, and exhibit Vimentin-dependent propagation, upon inhibition of the Hippo signaling pathway. The dediHeps re-differentiate into mature hepatocytes by forming aggregates, enabling reconstitution of hepatic tissues in vivo. Moreover, dediHeps have an unexpected differentiation potential into intestinal epithelial cells that can form organoids in three-dimensional culture and reconstitute colonic epithelia after transplantation. This remarkable plasticity will be useful in the study and treatment of intestinal metaplasia and related diseases in the liver.

DOI: https://doi.org/10.1038/s41467-024-47869-2
Cell Death Discov. 2024 May 13. 10(1): 228

HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis.

Weiwei Liu, Chaoqun Liu, Jun Xiao, Cheng Qian, Zhilin Chen, Wandie Lin, Yujie Zhang, Jianghua Wu, Rui Zhou, Liang Zhao.

Chemotherapy is an important therapuetic strategy for colorectal cancer (CRC), but chemoresistance severely affects its efficacy, and the underlying mechanism has not been fully elucidated. Increasing evidence suggests that lipid peroxidation imbalance-mediated ferroptosis is closely associated with chemoresistance. Hence, targeting ferroptosis pathways or modulating the tolerance to oxidative stress might be an effective strategy to reverse tumor chemoresistance. HtrA serine protease 1 (HTRA1) was screened out as a CRC progression- and chemoresistance-related gene. It is highly expressed in CRC cells and negatively correlated with the prognosis of CRC patients. Gain- and loss-of-function analyses demonstrated a stimulatory role of HTRA1 on the proliferation of CRC cells. The enrichment analysis of HTRA1-interacting proteins indicated the involvement of ferroptosis in the HTRA1-mediated chemoresistance. Moreover, electron microscope analysis, as well as the ROS and MDA levels in CRC cells also confirmed the effect of HTRA1 on ferroptosis. We also verified that HTRA1 could interact with SLC7A11 through its Kazal structural domain and up-regulate the expression of SLC7A11, which in turn inhibited the ferroptosis and leaded to the chemoresistance of CRC cells to 5-FU/L-OHP. Hence, we propose that HTRA1 may be a potential therapeutic target and a prognostic indicator in CRC.

DOI: https://doi.org/10.1038/s41420-024-01993-6
Int J Mol Sci. 2024 Apr 30. pii: 4883. [Epub ahead of print]25(9):

Overexpression of Fatty Acid Synthase Upregulates Glutamine-Fructose-6-Phosphate Transaminase 1 and O-Linked N-Acetylglucosamine Transferase to Increase O-GlcNAc Protein Glycosylation and Promote Colorectal Cancer Growth.

James Drury, Mariah E Geisen, Josiane Weber Tessmann, Piotr G Rychahou, Courtney O Kelson, Daheng He, Chi Wang, B Mark Evers, Yekaterina Y Zaytseva.

  Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro and in vivo. Consistently, expression of FASN significantly correlates with expression of GFPT1 and OGT in human CRC tissues. shRNA-mediated downregulation of GFPT1 and OGT inhibits cellular proliferation and the level of protein O-GlcNAcylation in vitro, and knockdown of GFPT1 leads to a significant decrease in tumor growth and metastasis in vivo. Pharmacological inhibition of GFPT1 and OGT leads to significant inhibition of cellular proliferation and colony formation in CRC cells. In summary, our results show that overexpression of FASN increases the expression of GFPT1 and OGT as well as the level of protein O-GlcNAcylation to promote progression of CRC; targeting the hexosamine biosynthesis pathway could be a therapeutic approach for this disease.

Keywords:  O-GlcNAcylation; colorectal cancer; fatty acid synthase; hexosamine biosynthesis

DOI:  https://doi.org/10.3390/ijms25094883
Nature. 2024 May;629(8012): 543-554

Decoding the interplay between genetic and non-genetic drivers of metastasis.

Panagiotis Karras, James R M Black, Nicholas McGranahan, Jean-Christophe Marine.

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.

DOI: https://doi.org/10.1038/s41586-024-07302-6