bims-instec 2023-12-10 papers

bims-instec

Biomed News

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

Issue of 2023‒12‒10
seven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.
PFKP is upregulated in 5-fluorouracil-resistant patients and suppresses the antitumor activity of 5-fluorouracil in colorectal cancer in vitro and in vivo.
Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy.
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.
Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling.
Integrating scRNA-seq and bulk RNA-seq to characterize infiltrating cells in the colorectal cancer tumor microenvironment and construct molecular risk models.
Single-cell transcriptomic analysis deciphers heterogenous cancer stem-like cells in colorectal cancer and their organ-specific metastasis.

iScience. 2023 Dec 15. 26(12): 108399

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.

Christina Plattner, Giorgia Lamberti, Peter Blattmann, Alexander Kirchmair, Dietmar Rieder, Zuzana Loncova, Gregor Sturm, Stefan Scheidl, Marieke Ijsselsteijn, Georgios Fotakis, Asma Noureen, Rebecca Lisandrelli, Nina Böck, Niloofar Nemati, Anne Krogsdam, Sophia Daum, Francesca Finotello, Antonios Somarakis, Alexander Schäfer, Doris Wilflingseder, Miguel Gonzalez Acera, Dietmar Öfner, Lukas A Huber, Hans Clevers, Christoph Becker, Henner F Farin, Florian R Greten, Ruedi Aebersold, Noel F C C de Miranda, Zlatko Trajanoski.

  Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.

Keywords:  Cancer; Cancer systems biology; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2023.108399
J Chemother. 2023 Dec 03. 1-13

PFKP is upregulated in 5-fluorouracil-resistant patients and suppresses the antitumor activity of 5-fluorouracil in colorectal cancer in vitro and in vivo.

Lili Deng, Yan Zhao, Wen Liu.

  As a long-established chemotherapy drug, 5-fluorouracil (5-FU) is widely used to clinically manage colorectal cancer (CRC). However, a substantial portion of patients develop 5-FU resistance at some stage, which poses a great challenge. Therefore, revealing the mechanisms that could guide the development of effective strategies to overcome 5-FU resistance is required. Here, we report that the expression of PFKP was higher in HCT116/5-FU CRC. Furthermore, genetic suppression of PFKP suppresses glycolysis, NF-κB activation, and expression of GLUT1 and HK2 in HCT116/5-FU cells. PFKP overexpression promotes glycolysis and expression of GLUT1 and HK2 via the NF-κB signaling pathway in HCT116 cells. Our functional assays demonstrated that PFKP silencing could sensitize HCT116/5-FU cells to 5-FU with an elevated population of apoptotic cells. In contrast, forced expression of PFKP conferred 5-FU resistance in HCT116 cells. Furthermore, PFKP silencing significantly inhibited CRC xenograft tumor growth. Notably, the combination of PFKP silencing and 5-FU inhibited tumor growth. Therefore, our results demonstrated that PFKP enhances 5-FU resistance by promoting glycolysis, indicating that PFKP could be a novel candidate for targeted therapy for 5-FU-resistant CRC.

Keywords:  5-FU resistance; Colorectal cancer; HCT116/5-FU cells; NF-κb; PFKP; apoptosis; glycolysis

DOI:  https://doi.org/10.1080/1120009X.2023.2288742
MedComm (2020). 2023 Dec;4(6): e427

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy.

Jiangjun Cao, Zhe Zhang, Li Zhou, Maochao Luo, Lei Li, Bowen Li, Edouard C Nice, Weifeng He, Shaojiang Zheng, Canhua Huang.

  Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.

Keywords:  cancer therapy; drug resistance; embryonic development; tumor development and progression

DOI:  https://doi.org/10.1002/mco2.427
Nat Med. 2023 Dec 05.

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.

GO42144 Investigator and Study Group

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

DOI: https://doi.org/10.1038/s41591-023-02696-8
Nat Commun. 2023 Dec 02. 14(1): 7963

Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling.

Chengyin Yuan, Aditya Rayasam, Alison Moe, Michael Hayward, Clive Wells, Aniko Szabo, Andrew Mackenzie, Nita Salzman, William R Drobyski.

Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract is not well known. Here, we describe the development of PCM in a murine model of chronic myelogenous leukemia (CML) that is driven by an inducible bcr-abl oncogene. Mechanistically, CML induces a proinflammatory state within the GI tract that results in the production of epithelial-derived IL-33. The binding of IL-33 to the decoy receptor ST2 leads to IL-9 production by type 2 innate lymphoid cells (ILC2) which is directly responsible for the induction of PCM in the colon and tissue remodeling in the small intestines, characterized by goblet and tuft cell hyperplasia along with expansion of mucosal mast cells. Thus, we demonstrate that an extra-intestinal disease can trigger an ILC2/IL-9 immune circuit, which induces PCM and regulates epithelial cell fate decisions in the GI tract.

DOI: https://doi.org/10.1038/s41467-023-43248-5
Aging (Albany NY). 2023 Dec 05. 15

Integrating scRNA-seq and bulk RNA-seq to characterize infiltrating cells in the colorectal cancer tumor microenvironment and construct molecular risk models.

Qi Wang, Yi-Fan Zhang, Chen-Long Li, Yang Wang, Li Wu, Xing-Ru Wang, Tai Huang, Ge-Liang Liu, Xing Chen, Qi Yu, Pei-Feng He.

  Colorectal cancer (CRC) is a malignancy that is both highly lethal and heterogeneous. Although the correlation between intra-tumoral genetic and functional heterogeneity and cancer clinical prognosis is well-established, the underlying mechanism in CRC remains inadequately understood. Utilizing scRNA-seq data from GEO database, we re-isolated distinct subsets of cells, constructed a CRC tumor-related cell differentiation trajectory, and conducted cell-cell communication analysis to investigate potential interactions across cell clusters. A prognostic model was built by integrating scRNA-seq results with TCGA bulk RNA-seq data through univariate, LASSO, and multivariate Cox regression analyses. Eleven distinct cell types were identified, with Epithelial cells, Fibroblasts, and Mast cells exhibiting significant differences between CRC and healthy controls. T cells were observed to engage in extensive interactions with other cell types. Utilizing the 741 signature genes, prognostic risk score model was constructed. Patients with high-risk scores exhibited a significant correlation with unfavorable survival outcomes, high-stage tumors, metastasis, and low responsiveness to chemotherapy. The model demonstrated a strong predictive performance across five validation cohorts. Our investigation involved an analysis of the cellular composition and interactions of infiltrates within the microenvironment, and we developed a prognostic model. This model provides valuable insights into the prognosis and therapeutic evaluation of CRC.

Keywords:  chemosensitivity; colorectal cancer; prognosis; single-cell RNA sequencing; tumour immune microenvironment

DOI:  https://doi.org/10.18632/aging.205263
Gut. 2023 Nov 30. pii: gutjnl-2023-330243. [Epub ahead of print]

Single-cell transcriptomic analysis deciphers heterogenous cancer stem-like cells in colorectal cancer and their organ-specific metastasis.

Rui Li, Xuefei Liu, Xudong Huang, Di Zhang, Ziming Chen, Jialiang Zhang, Ruihong Bai, Shaoping Zhang, Hongzhe Zhao, Zilan Xu, Lingxing Zeng, Lisha Zhuang, Shujuan Wen, Shaojia Wu, Mei Li, Zhixiang Zuo, Junzhong Lin, Dongxin Lin, Jian Zheng.

  OBJECTIVE: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.DESIGN: We performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). We also conducted immunofluorescence staining and functional experiments to examine the mechanism.
RESULTS: Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.
CONCLUSION: We uncover a mechanism for organ-specific CRC metastasis.

Keywords:  cancer stem cells; colorectal cancer; liver; metastasis; ovary

DOI:  https://doi.org/10.1136/gutjnl-2023-330243