bims-instec 2023-12-17 papers

bims-instec

Biomed News

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

Issue of 2023–12–17
seventeen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Plastic persisters: revival stem cells in colorectal cancer.
An oncogenic phenoscape of colonic stem cell polarization.
IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation of MAP1LC3B.
Single-cell profiling reveals the impact of genetic alterations on the differentiation of inflammation-induced colon tumors.
Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses.
Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.
Proteomic characterization of the colorectal cancer response to chemoradiation and targeted therapies reveals potential therapeutic strategies.
A liquid biopsy signature of circulating extracellular vesicles-derived RNAs predicts response to first line chemotherapy in patients with metastatic colorectal cancer.
A Novel TGF-β-Related Signature for Predicting Prognosis, Tumor Microenvironment, and Therapeutic Response in Colorectal Cancer.
Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt.
Single-cell map of dynamic cellular microenvironment of radiation-induced intestinal injury.
Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC-A New Opportunity to Predict Therapy Response.
Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.
Targeting cancer cell dormancy.
Targeting the TGF-β Signaling Axis in Metastatic Colorectal Cancer: Where Do We Stand?
Integrative analysis of single-cell and bulk RNA seq to reveal the prognostic model and tumor microenvironment remodeling mechanisms of cuproptosis-related genes in colorectal cancer.
Metabolic challengers selecting tumor-persistent cells.

Trends Cancer. 2023 Dec 08. pii: S2405-8033(23)00231-5. [Epub ahead of print]

Plastic persisters: revival stem cells in colorectal cancer.

Christopher J Tape.

  Colorectal cancer (CRC) is traditionally considered to be a genetically driven disease. However, nongenetic plasticity has recently emerged as a major driver of tumour initiation, metastasis, and therapy response in CRC. Central to these processes is a recently discovered cell type, the revival colonic stem cell (revCSC). In contrast to traditional proliferative CSCs (proCSCs), revCSCs prioritise survival over propagation. revCSCs play an essential role in primary tumour formation, metastatic dissemination, and nongenetic chemoresistance. Current evidence suggests that CRC tumours leverage intestinal stem cell plasticity to both proliferate (via proCSCs) when unchallenged and survive (via revCSCs) in response to cell-extrinsic pressures. Although revCSCs likely represent a major source of therapeutic failure in CRC, our increasing knowledge of this important stem cell fate provides novel opportunities for therapeutic intervention.

Keywords:  colorectal cancer (CRC); drug-tolerant persister (DTP); metastasis; plasticity; revival stem cells

DOI:  https://doi.org/10.1016/j.trecan.2023.11.003
Cell. 2023 Dec 07. pii: S0092-8674(23)01221-7. [Epub ahead of print]186(25): 5554-5568.e18

An oncogenic phenoscape of colonic stem cell polarization.

Xiao Qin, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Jeroen Claus, Christopher J Tape.

  Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU)+ revival colonic stem cells (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRASG12D or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12D collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.

Keywords:  CRC; cell plasticity; cell-cell signaling; cell-fate polarization; colonic stem cell; colorectal cancer; cue-signal-response; organoid; single-cell analysis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2023.11.004
Cell Mol Gastroenterol Hepatol. 2023 Dec 09. pii: S2352-345X(23)00214-X. [Epub ahead of print]

IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation of MAP1LC3B.

Louis R Parham, Patrick A Williams, Kay Katada, Shaneice K Nettleford, Priya Chatterji, Kofi K Acheampong, Charles H Danan, Xianghui Ma, Lauren A Simon, Kaitlyn E Naughton, Tatiana Karakasheva, Emily A McMillan, Kelly A Whelan, Donita C Brady, Sydney M Shaffer, Kathryn E Hamilton.

BACKGROUND & AIMS: The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies demonstrate autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration.
METHODS: We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein IMP1. The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of Atg7. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single molecule fluorescent in situ hybridization (smFISH).
RESULTS: Epithelial Imp1 deletion reduced Lgr5+ cell frequency but enhanced both organoid formation efficiency and in vivo regeneration following irradiation. We confirmed prior studies demonstrating increased autophagy with IMP1 deletion. Deletion of Atg7 reversed the enhanced regeneration observed with Imp1 deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein Microtubule Associated Protein 1 Light Chain 3 Beta (MAP1LC3B). Furthermore, immunofluorescence imaging coupled with smFISH demonstrated IMP1 colocalization with MAP1LC3B transcripts at homeostasis. Stress induction led to decreased co-localization.
CONCLUSIONS: Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.

DOI: https://doi.org/10.1016/j.jcmgh.2023.12.001
bioRxiv. 2023 Dec 02. pii: 2023.11.30.569463. [Epub ahead of print]

Single-cell profiling reveals the impact of genetic alterations on the differentiation of inflammation-induced colon tumors.

Ahmed H Ghobashi, Rosie Lanzloth, Christopher A Ladaika, Heather M O'Hagan.

Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (Min ApcΔ716/+ ) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAF V600E mutation ( BRAF FV600E Lgr5 tm1(Cre/ERT2)Cle Min ApcΔ716/+ , BLM) or knocking out Msh2 ( Msh2 LoxP/LoxP Vil1-cre Min ApcΔ716/+ , MSH2KO) in the Min model altered colon tumor differentiation. Using single cell RNA-sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the stem cell population. In contrast, MSH2KO tumors were characterized by an increased stem cell population that had higher WNT signaling activity compared to Min tumors. Additionally, comparative analysis of single-cell transcriptomics revealed that BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we were able to identify additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer.

DOI: https://doi.org/10.1101/2023.11.30.569463
Cell. 2023 Dec 07. pii: S0092-8674(23)01220-5. [Epub ahead of print]186(25): 5606-5619.e24

Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses.

María Ramos Zapatero, Alexander Tong, James W Opzoomer, Rhianna O'Sullivan, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Callum Nattress, Xiao Qin, Jeroen Claus, Daniel Hochhauser, Smita Krishnaswamy, Christopher J Tape.

  Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post-translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed "Trellis"-a highly scalable, tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity-shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy.

Keywords:  CAFs; PDOs; PTM signaling; Trellis; cancer associated fibroblasts; chemoresistance; mass cytometry; patient-derived organoids; plasticity; scRNA-seq; single-cell screening

DOI:  https://doi.org/10.1016/j.cell.2023.11.005
Cell. 2023 Dec 07. pii: S0092-8674(23)01222-9. [Epub ahead of print]186(25): 5620-5637.e16

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Cody N Heiser, Alan J Simmons, Frank Revetta, Eliot T McKinley, Marisol A Ramirez-Solano, Jiawei Wang, Harsimran Kaur, Justin Shao, Gregory D Ayers, Yu Wang, Sarah E Glass, Naila Tasneem, Zhengyi Chen, Yan Qin, William Kim, Andrea Rolong, Bob Chen, Paige N Vega, Julia L Drewes, Nicholas O Markham, Nabil Saleh, Fotis Nikolos, Simon Vandekar, Angela L Jones, M Kay Washington, Joseph T Roland, Keith S Chan, Thomas Schürpf, Cynthia L Sears, Qi Liu, Martha J Shrubsole, Robert J Coffey, Ken S Lau.

  Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.

Keywords:  colorectal cancer; immune exclusion; microsatellite instability; multiplex imaging; mutations; spatial transcriptomics; stem cells; tumor evolution; tumor progression

DOI:  https://doi.org/10.1016/j.cell.2023.11.006
Cell Rep Med. 2023 Dec 06. pii: S2666-3791(23)00505-0. [Epub ahead of print] 101311

Proteomic characterization of the colorectal cancer response to chemoradiation and targeted therapies reveals potential therapeutic strategies.

Yan Li, Bing Wang, Fahan Ma, Dongxian Jiang, Ying Wang, Kai Li, Subei Tan, Jinwen Feng, Yunzhi Wang, Zhaoyu Qin, Ganfei Xu, Sha Tian, Xiaolei Zhang, Chen Xu, Jiaxue Wu, Jianmin Xu, Yingyong Hou, Chen Ding.

  Chemoradiation and targeted therapies are the major treatments for colorectal cancer (CRC); however, molecular properties associated with therapy resistance are incompletely characterized. Here, we profile the proteome of 254 tumor tissues from patients with CRC undergoing chemotherapy, chemoradiation, or chemotherapy combined with targeted therapy. Proteome-based classification reveals four subtypes featured with distinct biological and therapeutic characteristics. The integrative analysis of CRC cell lines and clinical samples indicates that immune regulation is significantly associated with drug sensitivity. HSF1 can increase DNA damage repair and cell cycle, thus inducing resistance to radiation, while high expression of HDAC6 is negatively associated with response of cetuximab. Furthermore, we develop prognostic models with high accuracy to predict the therapeutic response, further validated by parallel reaction monitoring (PRM) assay in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemoradiation and targeted therapy in CRC.

Keywords:  chemoradiation and targeted therapies; colorectal cancer; parallel reaction monitoring; prognostic models; proteome-based classification; therapeutic response

DOI:  https://doi.org/10.1016/j.xcrm.2023.101311
Mol Cancer. 2023 Dec 07. 22(1): 199

A liquid biopsy signature of circulating extracellular vesicles-derived RNAs predicts response to first line chemotherapy in patients with metastatic colorectal cancer.

Ya'nan Yang, Jieyun Zhang, Wen Zhang, Yixuan Wang, Yujia Zhai, Yan Li, Wenhua Li, Jinjia Chang, Xiaoying Zhao, Mingzhu Huang, Qirong Geng, Yue Yang, Zhe Gong, Nuoya Yu, Wei Shen, Qian Li, Shenglin Huang, Weijian Guo.

   BACKGROUND: Colorectal cancer (CRC) is one of the most threatening tumors in the world, and chemotherapy remains dominant in the treatment of metastatic CRC (mCRC) patients. The purpose of this study was to develop a biomarker panel to predict the response of the first line chemotherapy in mCRC patients.
METHODS: Totally 190 mCRC patients treated with FOLFOX or XEOLX chemotherapy in 3 different institutions were included. We extracted the plasma extracellular vesicle (EV) RNA, performed RNA sequencing, constructed a model and generated a signature through shrinking the number of variables by the random forest algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm in the training cohort (n = 80). We validated it in an internal validation cohort (n = 62) and a prospective external validation cohort (n = 48).
RESULTS: We established a signature consisted of 22 EV RNAs which could identify responders, and the area under the receiver operating characteristic curve (AUC) values was 0.986, 0.821, and 0.816 in the training, internal validation, and external validation cohort respectively. The signature could also identify the progression-free survival (PFS) and overall survival (OS). Besides, we constructed a 7-gene signature which could predict tumor response to first-line oxaliplatin-containing chemotherapy and simultaneously resistance to second-line irinotecan-containing chemotherapy.
CONCLUSIONS: The study was first to develop a signature of EV-derived RNAs to predict the response of the first line chemotherapy in mCRC with high accuracy using a non-invasive approach, indicating that the signature could help to select the optimal regimen for mCRC patients.

Keywords:  Chemotherapy; Colorectal cancer; Extracellular vesicles; Prediction; Signature

DOI:  https://doi.org/10.1186/s12943-023-01875-y
Biochem Genet. 2023 Dec 07.

A Novel TGF-β-Related Signature for Predicting Prognosis, Tumor Microenvironment, and Therapeutic Response in Colorectal Cancer.

Baorui Tao, Chenhe Yi, Yue Ma, Yitong Li, Bo Zhang, Yan Geng, Zhenmei Chen, Xiaochen Ma, Jinhong Chen.

  The transforming growth factor beta (TGF-β) signaling plays a critical role in immune evasion and tumor progression. However, its modulatory influences on prognosis, tumor microenvironment (TME), and therapeutic efficacy remain unknown in colorectal cancer (CRC). We summarized TGF-β-related genes and comprehensively estimated their expression pattern in 2142 CRC samples from 9 datasets. Two distinct cluster patterns were divided and biological characteristics of each pattern were further analyzed. Then, to quantify the TGF-β cluster pattern of individual CRC patient, we generated the TGF-β score (TGFBscore) model based on TGF-β cluster pattern-relevant differentially expressed genes (DEGs). Subsequently, we conducted correlation analysis for TGFBscore and clinical prognosis, consensus molecular subtypes (CMSs), TME characteristics, liver metastasis, drug response, and immunotherapeutic efficacy in CRC. We illustrated transcriptional and genetic alterations of TGF-β-relevant genes, which were closely linked with carcinogenic pathways. We identified two different TGF-β cluster patterns, characterized by a high and a low TGFBscore. The TGFBscore-high group was significantly linked with worse patient survival, epithelial-mesenchymal transition (EMT) activation, liver metastasis tendency, and the infiltration of immunosuppressive cells (regulatory T cells [Tregs], M2 macrophages, cancer-associated fibroblasts [CAFs], and myeloid-derived suppressor cells [MDSCs]), while the TGFBscore-low group was linked with a survival advantage, epithelial phenotype, early CRC staging, and the infiltration of immune-activated cells (B cell, CD4 T cell, natural killer T [NKT] cell, and T helper 1 [Th1] cell). In terms of predicting drug response, TGFBscore negatively correlated (sensitive to TGFBscore-high group) with drugs targeting PI3K/mTOR, JNK and p38, RTK signaling pathways, and positively correlated (sensitive to TGFBscore-low group) with drugs targeting EGFR signaling pathway. Also, TGFBscore could predict the efficacy of different anti-tumor therapies. TGFBscore-low patients might benefit more from anti-PDL1 immunotherapy, adjuvant chemotherapy (ACT), and ERBB targeted therapy, whereas TGFBscore-high patients might benefit more from antiangiogenic targeted therapy. Our study constructed a novel TGF-β scoring model that could predict prognosis, liver metastasis tendency, and TME characteristics for CRC patients. More importantly, this work emphasizes the potential clinical utility of TGFBscore in evaluating the efficacy of chemotherapy, targeted therapy, and immunotherapy, guiding individualized precision treatment in CRC.

Keywords:  Colorectal cancer; Immunotherapy; Liver metastasis; Prognosis; TGFBscore; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10528-023-10591-7
Elife. 2023 Dec 08. pii: e85478. [Epub ahead of print]12

Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt.

Louis Gall, Carrie Duckworth, Ferran Jardi, Lieve Lammens, Aimee Parker, Ambra Bianco, Holly Kimko, David Mark Pritchard, Carmen Pin.

  The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43 and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation and migration and leads to loss of barrier integrity. During recovery, our in-silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.

Keywords:  computational biology; mouse; systems biology

DOI:  https://doi.org/10.7554/eLife.85478
Commun Biol. 2023 Dec 09. 6(1): 1248

Single-cell map of dynamic cellular microenvironment of radiation-induced intestinal injury.

Hao Lu, Hua Yan, Xiaoyu Li, Yuan Xing, Yumeng Ye, Siao Jiang, Luyu Ma, Jie Ping, Hongyan Zuo, Yanhui Hao, Chao Yu, Yang Li, Gangqiao Zhou, Yiming Lu.

Intestine is a highly radiation-sensitive organ that could be injured during the radiotherapy for pelvic, abdominal, and retroperitoneal tumors. However, the dynamic change of the intestinal microenvironment related to radiation-induced intestine injury (RIII) is still unclear. Using single-cell RNA sequencing, we pictured a dynamic landscape of the intestinal microenvironment during RIII and regeneration. We showed that the various cell types of intestine exhibited heterogeneous radiosensitivities. We revealed the distinct dynamic patterns of three subtypes of intestinal stem cells (ISCs), and the cellular trajectory analysis suggested a complex interconversion pattern among them. For the immune cells, we found that Ly6c+ monocytes can give rise to both pro-inflammatory macrophages and resident macrophages after RIII. Through cellular communication analysis, we identified a positive feedback loop between the macrophages and endothelial cells, which could amplify the inflammatory response induced by radiation. Besides, we identified different T cell subtypes and revealed their role in immunomodulation during the early stage of RIII through inflammation and defense response relevant signaling pathways. Overall, our study provides a valuable single-cell map of the multicellular dynamics during RIII and regeneration, which may facilitate the understanding of the mechanism of RIII.

DOI: https://doi.org/10.1038/s42003-023-05645-w
Cancers (Basel). 2023 Nov 28. pii: 5623. [Epub ahead of print]15(23):

Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC-A New Opportunity to Predict Therapy Response.

Jakub Kryczka, Joanna Boncela.

   BACKGROUND: Our previous findings proved that ABCC4 and ABCG2 proteins present much more complex roles in colorectal cancer (CRC) than typically cancer-associated functions as drug exporters. Our objective was to evaluate their predictive/diagnostic potential.
METHODS: CRC patients' transcriptomic data from the Gene Expression Omnibus database (GSE18105, GSE21510 and GSE41568) were discriminated into two subpopulations presenting either high expression levels of ABCC4 (ABCC4 High) or ABCG2 (ABCG2 High). Subpopulations were analysed using various bioinformatical tools and platforms (KEEG, Gene Ontology, FunRich v3.1.3, TIMER2.0 and STRING 12.0).
RESULTS: The analysed subpopulations present different gene expression patterns. The protein-protein interaction network of subpopulation-specific genes revealed the top hub proteins in ABCC4 High: RPS27A, SRSF1, DDX3X, BPTF, RBBP7, POLR1B, HNRNPA2B1, PSMD14, NOP58 and EIF2S3 and in ABCG2 High: MAPK3, HIST2H2BE, LMNA, HIST1H2BD, HIST1H2BK, HIST1H2AC, FYN, TLR4, FLNA and HIST1H2AJ. Additionally, our multi-omics analysis proved that the ABCC4 expression correlates with substantially increased tumour-associated macrophage infiltration and sensitivity to FOLFOX treatment.
CONCLUSIONS: ABCC4 and ABCG2 may be used to distinguish CRC subpopulations that present different molecular and physiological functions. The ABCC4 High subpopulation demonstrates significant EMT reprogramming, RNA metabolism and high response to DNA damage stimuli. The ABCG2 High subpopulation may resist the anti-EGFR therapy, presenting higher proteolytical activity.

Keywords:  ABCC4; ABCG2; CRC; CRC diagnostic and prognostic biomarkers; CRC subpopulations; immune cell infiltration; metastasis

DOI:  https://doi.org/10.3390/cancers15235623
Nat Commun. 2023 Dec 13. 14(1): 8075

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

Yu Muta, Juan F Linares, Anxo Martinez-Ordoñez, Angeles Duran, Tania Cid-Diaz, Hiroto Kinoshita, Xiao Zhang, Qixiu Han, Yuki Nakanishi, Naoko Nakanishi, Thekla Cordes, Gurpreet K Arora, Marc Ruiz-Martinez, Miguel Reina-Campos, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Christian M Metallo, Timothy F Osborne, Maria T Diaz-Meco, Jorge Moscat.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

DOI: https://doi.org/10.1038/s41467-023-43690-5
Nat Rev Cancer. 2023 Dec 07.

Targeting cancer cell dormancy.

Judith Agudo, Julio A Aguirre-Ghiso, Mickie Bhatia, Lewis A Chodosh, Ana Luísa Correia, Christoph A Klein.

DOI: https://doi.org/10.1038/s41568-023-00642-x
Int J Mol Sci. 2023 Dec 04. pii: 17101. [Epub ahead of print]24(23):

Targeting the TGF-β Signaling Axis in Metastatic Colorectal Cancer: Where Do We Stand?

Kostas A Papavassiliou, Donatella Delle Cave, Athanasios G Papavassiliou.

Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide [...].

DOI: https://doi.org/10.3390/ijms242317101
Aging (Albany NY). 2023 Dec 08. 15

Integrative analysis of single-cell and bulk RNA seq to reveal the prognostic model and tumor microenvironment remodeling mechanisms of cuproptosis-related genes in colorectal cancer.

Bowen Chu, Yaohui Wang, Jiwen Yang, Bohan Dong.

   BACKGROUND: Recently, there has been a great deal interest in cuproptosis, a form of programmed cell death that is mediated by copper. The specific mechanism through which cuproptosis-related genes impact the development of colorectal cancer (CRC) remains unknown.
METHODS: Here, we combined bulk RNA-seq with scRNA-seq to investigate the CRGs functions within CRC. A number of 61 cuproptosis-related genes were chosen for further investigation. Nine prognostic CRGs were identified by Lasso-Cox. The RiskScore was created and the patients have been separated into two different groups, low- and high-RiskScore group. The CIBERSORT, ESTIMATE, MCP-counter, TIDE, and IPS have been employed to score the TME, and GSVA and GSEA were utilized to evaluate the pathway within the both groups. Further, we used cell communication analysis to explore the tumor microenvironment remodeling mechanisms of the COX17 and DLAT based on scRNA-seq. Finally, we used IHC and qPCR to validate the expression of COX17 and DLAT.
RESULTS: AOC3, CCS, CDKN2A, COX11, COX17, COX19, DLD, DLAT, and PDHB have been recognized as prognostic CRGs in CRC. The high-risk group exhibited the worst prognosis, an immune-deficient phenotype, and were more resistant to ICB treatment. Further, scRNA-seq analysis revealed that elevated expression of COX17 in CD4-CXCL13Tfh could contribute to the immune evasion while DLAT had the opposite effect, reversing T cell exhaustion and inducing pyroptosis to boost CD8-GZMKT infiltration.
CONCLUSIONS: The current investigation has developed a prognostic framework utilizing cuproptosis-related genes that is highly effective in predicting prognosis, TME type, and response to immunotherapy in CRC patients. Furthermore, our study reveals a novel finding that elevated levels of COX17 expression within CD4-CXCL13 T cells in CRC mediates T cell exhaustion and Treg infiltration, while DLAT has been found to facilitate the anti-tumor immunity activation through the T cell exhaustion reversal and the induction of pyroptosis.

Keywords:  colorectal cancer; copper metabolism; cuproptosis; t cell exhaustion; tumor microenvironment

DOI:  https://doi.org/10.18632/aging.205324
Trends Endocrinol Metab. 2023 Dec 09. pii: S1043-2760(23)00244-8. [Epub ahead of print]

Metabolic challengers selecting tumor-persistent cells.

Caterina Mancini, Giulia Lori, Erica Pranzini, Maria Letizia Taddei.

  Resistance to anticancer therapy still represents one of the main obstacles to cancer treatment. Numerous components of the tumor microenvironment (TME) contribute significantly to the acquisition of drug resistance. Microenvironmental pressures arising during cancer evolution foster tumor heterogeneity (TH) and facilitate the emergence of drug-resistant clones. In particular, metabolic pressures arising in the TME may favor epigenetic adaptations supporting the acquisition of persistence features in tumor cells. Tumor-persistent cells (TPCs) are characterized by high phenotypic and metabolic plasticity, representing a noticeable advantage in chemo- and radio-resistance. Understanding the crosslink between the evolution of metabolic pressures in the TME, epigenetics, and TPC evolution is significant for developing novel therapeutic strategies specifically targeting TPC vulnerabilities to overcome drug resistance.

Keywords:  epigenetics; metabolism; therapy resistance; tumor microenvironment; tumor-persistent cells

DOI:  https://doi.org/10.1016/j.tem.2023.11.005