bims-instec 2023-10-01 papers

bims-instec

Biomed News

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

Issue of 2023–10–01
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer.
Network-guided Therapeutics to Differentiate Colorectal Cancer Stem Cells.
Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression.
Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.
A Novel Lipid Metabolism and Endoplasmic Reticulum Stress-Related Risk Model for Predicting Immune Infiltration and Prognosis in Colorectal Cancer.
B7-H3 at the crossroads between tumor plasticity and colorectal cancer progression: a potential target for therapeutic intervention.
Piezo1 activates noncanonical EGFR endocytosis and signaling.
Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly.
Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites.

Nat Commun. 2023 09 23. 14(1): 5945

Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer.

Lucia Taraborrelli, Yasin Şenbabaoğlu, Lifen Wang, Junghyun Lim, Kerrigan Blake, Noelyn Kljavin, Sarah Gierke, Alexis Scherl, James Ziai, Erin McNamara, Mark Owyong, Shilpa Rao, Aslihan Karabacak Calviello, Daniel Oreper, Suchit Jhunjhunwala, Guillem Argiles, Johanna Bendell, Tae Won Kim, Fortunato Ciardiello, Matthew J Wongchenko, Frederic J de Sauvage, Felipe de Sousa E Melo, Yibing Yan, Nathaniel R West, Aditya Murthy.

Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

DOI: https://doi.org/10.1038/s41467-023-41618-7
bioRxiv. 2023 Sep 21. pii: 2023.09.13.557628. [Epub ahead of print]

Network-guided Therapeutics to Differentiate Colorectal Cancer Stem Cells.

Saptarshi Sinha, Joshua Alcantara, Kevin Perry, Vanessa Castillo, Celia R Espinoza, Sahar Taheri, Eleadah Vidales, Courtney Tindle, Adel Adel, Siamak Amirfakhri, Joseph R Sawires, Jerry Yang, Michael Bouvet, Debashis Sahoo, Pradipta Ghosh.

The curative potential of differentiation therapy has been recognized in hematologic malignancies, but not in solid tumors. Using colorectal cancers (CRCs) as an example, here we outline an unbiased network-based approach to track, differentiate and selectively target cancer stem cells (CSCs). A transcriptomic network is built with the intention to identify therapeutic perturbations that can reinstate the expression of CDX2, a transcription factor whose loss identifies poorly differentiated (CSC-enriched) CRCs, and whose reinstatement is predicted to reduce the risk of death/relapse by 50%. The top candidate target, when engaged with a clinical-grade drug, predictably shifts the network, induces CDX2 and crypt differentiation and shows cytotoxicity with a surprising degree of selectivity towards CDX2-negative models (CRC cell lines, xenotransplants in mice, and patient-derived organoids; PDOs). Potential for effective pairing of therapeutic efficacy (IC50) and biomarker (CDX2-low state) is confirmed in PDOs using multivariate analyses. A 50-gene signature of therapeutic response shows that CDX2-reinstatement therapy is expected to translate into a ~50% reduction in the risk of mortality/recurrence. We conclude that CDX2-reinstatement selectively triggers differentiation and death of colorectal CSCs, and in doing so, this network-guided approach identifies a first-in-class differentiation therapy agent in solid tumors.

DOI: https://doi.org/10.1101/2023.09.13.557628
Cancer Discov. 2023 Sep 28.

Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression.

Wen-Hao Hsu, Kyle A LaBella, Yiyun Lin, Ping Xu, Rumi Lee, Cheng-En Hsieh, Lei Yang, Ashley Zhou, Jonathan M Blecher, Chang-Jiun Wu, Kangyu Lin, Xiaoying Shang, Shan Jiang, Denise J Spring, Yan Xia, Peiwen Chen, John Paul Shen, Scott Kopetz, Ronald A DePinho.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* suppresses anti-tumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAFs) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) which upregulates the expression of the pro-adipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce vascular endothelial growth factor A (VEGFA) to spur angiogenesis. In KRAS*-driven CRC mouse models, genetic or pharmacological neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human CRC, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven CRC.

DOI: https://doi.org/10.1158/2159-8290.CD-22-1467
Biochem Biophys Res Commun. 2023 Sep 23. pii: S0006-291X(23)01101-4. [Epub ahead of print]681 127-135

Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.

Liping Yan, Jian Zheng, Qingyu Wang, Hua Hao.

  Cancer-associated fibroblasts (CAFs) are mesenchymal cells in the tumor microenvironment (TME). CAFs are the most abundant cellular components in the TME of solid tumors. They affect the progression and course of chemotherapy and radiotherapy in various types of tumors including colorectal cancer (CRC). CAFs can promote tumor proliferation, invasion, and metastasis; protect tumor cells from immune surveillance; and resist tumor cell apoptosis caused by chemotherapy, resulting in drug resistance to chemotherapy. In recent years, researchers have become increasingly interested CAF functions and have conducted extensive research. However, compared to other types of malignancies, our understanding of the interaction between CRC cells and CAFs remains limited. Therefore, we searched the relevant literature published in the past 10 years, and reviewed the origin, biological characteristics, heterogeneity, role in the TME, and potential therapeutic targets of CAFs, to aid future research on CAFs and tumors.

Keywords:  Cancer-associated fibroblasts; Colorectal cancer; Signaling pathways; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbrc.2023.09.065
Int J Mol Sci. 2023 Sep 08. pii: 13854. [Epub ahead of print]24(18):

A Novel Lipid Metabolism and Endoplasmic Reticulum Stress-Related Risk Model for Predicting Immune Infiltration and Prognosis in Colorectal Cancer.

Haoran Jin, Bihan Xia, Jin Wang, Shaochong Qi, Weina Jing, Kai Deng, Jinlin Yang.

  Lipid metabolism and endoplasmic reticulum stress exhibit crosstalk in various cancer types, which are closely associated with the progression of colorectal cancer (CRC). This study constructs a prognostic signature based on lipid metabolism and endoplasmic reticulum stress-related genes (LERGs) for CRC patients, aiming to predict the prognosis and immune response. RNA sequencing and clinical data from the TCGA and GEO databases were analyzed to identify differentially expressed LERGs with prognostic relevance using univariate Cox regression. Subsequently, a risk model was developed using the LASSO regression. CRC patients were stratified into low-risk and high-risk groups based on risk scores, with the high-risk cohort demonstrating a poorer clinical prognosis in multiple databases. The risk model showed robust correlations with clinical features, gene mutations, and treatment sensitivity. Significant differences in immune cell infiltration and the expression of immune-related factors were also detected between risk groups, and elevated scores of cytokines and failure factors were detected in single-cell RNA sequencing analysis. This research indicates that lipid metabolism and endoplasmic reticulum stress in CRC are correlated with tumor progression, an immunosuppressive landscape, and alterations of drug sensitivity. The developed risk model can serve as a powerful prognostic tool, offering critical insights for refining clinical management and optimizing treatment in CRC patients.

Keywords:  colorectal cancer; drug sensitivity; endoplasmic reticulum stress; immune infiltration; immunotherapy; lipid metabolism; prognostic prediction model

DOI:  https://doi.org/10.3390/ijms241813854
Cancer Metastasis Rev. 2023 Sep 28.

B7-H3 at the crossroads between tumor plasticity and colorectal cancer progression: a potential target for therapeutic intervention.

Elizabeth Varghese, Samson Mathews Samuel, Aranka Brockmueller, Mehdi Shakibaei, Peter Kubatka, Dietrich Büsselberg.

  B7-H3 (B7 homology 3 protein) is an important transmembrane immunoregulatory protein expressed in immune cells, antigen-presenting cells, and tumor cells. Studies reveal a multifaceted role of B7-H3 in tumor progression by modulating various cancer hallmarks involving angiogenesis, immune evasion, and tumor microenvironment, and it is also a promising candidate for cancer immunotherapy. In colorectal cancer (CRC), B7-H3 has been associated with various aspects of disease progression, such as evasion of tumor immune surveillance, tumor-node metastasis, and poor prognosis. Strategies to block or interfere with B7-H3 in its immunological and non-immunological functions are under investigation. In this study, we explore the role of B7-H3 in tumor plasticity, emphasizing tumor glucose metabolism, angiogenesis, epithelial-mesenchymal transition, cancer stem cells, apoptosis, and changing immune signatures in the tumor immune landscape. We discuss how B7-H3-induced tumor plasticity contributes to immune evasion, metastasis, and therapy resistance. Furthermore, we delve into the most recent advancements in targeting B7-H3-based tumor immunotherapy as a potential approach to CRC treatment.

Keywords:  B7-H3; Colorectal cancer; Drug resistance; Immunomodulation; Tumor plasticity, immune checkpoint

DOI:  https://doi.org/10.1007/s10555-023-10137-8
Sci Adv. 2023 Sep 29. 9(39): eadi1328

Piezo1 activates noncanonical EGFR endocytosis and signaling.

Carlos Pardo-Pastor, Jody Rosenblatt.

EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.

DOI: https://doi.org/10.1126/sciadv.adi1328
World J Gastroenterol. 2023 Sep 21. 29(35): 5104-5124

Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly.

Cong-Yu Zhang, Rui Zhang, Li Zhang, Zi-Mo Wang, Hong-Zhi Sun, Zheng-Guo Cui, Hua-Chuan Zheng.

   BACKGROUND: Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.
AIM: To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.
METHODS: We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.
RESULTS: Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.
CONCLUSION: REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.

Keywords:  Aggressive behavior; Chemoresistance; Colorectal cancer; Epidermal growth factor receptor signal; Lipid droplet formation; Prognosis; Regenerating gene 4

DOI:  https://doi.org/10.3748/wjg.v29.i35.5104
J Exp Med. 2023 Dec 04. pii: e20221015. [Epub ahead of print]220(12):

Retinoic acid drives intestine-specific adaptation of effector ILC2s originating from distant sites.

Nikhat Shaikh, Alex Waterhölter, Ann-Christin Gnirck, Martina Becker, Virginia Adamiak, Lena Henneken, Malte Wunderlich, Wiebke Hartmann, Lara Linnemann, Tobias B Huber, Christian F Krebs, Ulf Panzer, Richard M Locksley, Christoph Wilhelm, Minka Breloer, Jan-Eric Turner.

Adaptation of immune cells to tissue-specific microenvironments is a crucial process in homeostasis and inflammation. Here, we show that murine effector type 2 innate lymphoid cells (ILC2s) from various organs are equally effective in repopulating ILC2 niches in other anatomical locations where they adapt tissue-specific phenotypes of target organs. Single-cell transcriptomics of ILC2 populations revealed upregulation of retinoic acid (RA) signaling in ILC2s during adaptation to the small intestinal microenvironment, and RA signaling mediated reprogramming of kidney effector ILC2s toward the small intestinal phenotype in vitro and in vivo. Inhibition of intestinal ILC2 adaptation by blocking RA signaling impaired worm expulsion during Strongyloides ratti infection, indicating functional importance of ILC2 tissue imprinting. In conclusion, this study highlights that effector ILC2s retain the ability to adapt to changing tissue-specific microenvironments, enabling them to exert tissue-specific functions, such as promoting control of intestinal helminth infections.

DOI: https://doi.org/10.1084/jem.20221015