Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation

Wu, Chenming; Rakhshandehroo, Taha; Wettersten, Hiromi I.; Campos, Alejandro D.; Schalscha, Tami von; Jain, Shashi; Yu, Ziqi; Tan, Jiali; Mose, Evangeline; Childers, Betzaira G.; Lowy, Andrew M.; Weis, Sara M.; Cheresh, David A.

doi:10.1038/s41556-022-01055-y

Cited by 12 publications

(10 citation statements)

References 54 publications

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“…Their findings revealed that the adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identifies a candidate cell of origin of relapse after treatment in CRC that they called HRC. Similar findings have been obtained by Wu C. from the Sara M. Weis and David A. Cheresh group, studying how microenvironmental stresses affect tumor initiation and progression of aggressive pancreatic cancer cells [ 44 ]. These authors have recently reported that the harsh microenvironments of the body can push certain pancreatic cancer cells to overcome the stress of being isolated and make them more adept at initiating and forming new tumor colonies.…”

Section: Discussionsupporting

confidence: 83%

Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

Moreno-Londoño

Castañeda-Patlán

Sarabia-Sánchez

et al. 2023

IJMS

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The presence of cancer stem cells (CSCs) has been associated with the induction of drug resistance and disease recurrence after therapy. 5-Fluorouracil (5FU) is widely used as the first-line treatment of colorectal cancer (CRC). However, its effectiveness may be limited by the induction of drug resistance in tumor cells. The Wnt pathway plays a key role in the development and CRC progression, but it is not clearly established how it is involved in CSCs resistance to treatment. This work aimed to investigate the role played by the canonical Wnt/β-catenin pathway in CSCs resistance to 5FU treatment. Using tumor spheroids as a model of CSCs enrichment of CRC cell lines with different Wnt/β-catenin contexts, we found that 5FU induces in all CRC spheroids tested cell death, DNA damage, and quiescence, but in different proportions for each one: RKO spheroids were very sensitive to 5FU, while SW480 were less susceptible, and the SW620 spheroids, the metastatic derivative of SW480 cells, displayed the highest resistance to death, high clonogenic capacity, and the highest ability for regrowth after 5FU treatment. Activating the canonical Wnt pathway with Wnt3a in RKO spheroids decreased the 5FU-induced cell death. But the Wnt/β-catenin pathway inhibition with Adavivint alone or in combination with 5FU in spheroids with aberrant activation of this pathway produced a severe cytostatic effect compromising their clonogenic capacity and diminishing the stem cell markers expression. Remarkably, this combined treatment also induced the survival of a small cell subpopulation that could exit the arrest, recover SOX2 levels, and re-grow after treatment.

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Section: Discussionsupporting

confidence: 83%

Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

Moreno-Londoño

Castañeda-Patlán

Sarabia-Sánchez

et al. 2023

IJMS

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“…As a poor prognostic indicator, FAK was able to drive desmoplasia, immunosuppression, and metastasis of PDAC by regulating the expression of matrix metalloproteinases (MMP), PI3K/AKT, and other signals [ 184 , 185 ]. A recent study uncovered that PDAC cells exposed to environmental stress or chemotherapy could induce fibronectin expression by up-regulating lysophosphatidic acid receptor 4 (LPAR4), promoting an ECM-enriched niche and therapeutic resistance [ 186 ]. MMPs, over-expressed mainly by CAFs, are thought to lead to massive breakdown of the ECM, neovascularization, tumor spread, and metastasis.…”

Section: More Complete Immunophenotyping: Enrolling the Matrixmentioning

confidence: 99%

Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept

Luo,

Wen,

2024

J Exp Clin Cancer Res

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, immune cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this is a major cause of therapy resistance and poor prognosis. In recent years, research has advanced our understanding of the signaling mechanism by which TIME components interact with the tumor and the evolution of immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs as “cold” and “hot” to a more comprehensive approach of immunophenotyping that considers all the cells and matrix components. This is key to improving the clinical efficacy of PDAC treatments. In this review, we elaborate on various TIME components in PDAC, the signaling mechanisms underlying their interactions, and the latest research into PDAC immunophenotyping. A deep understanding of these network interactions will contribute to the effective combination of TIME-based therapeutic approaches, such as immune checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid cells, CAF reprogramming, and stromal normalization. By selecting the appropriate integrated therapies based on precise immunophenotyping, significant advances in the future treatment of PDAC are possible.

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“…The mesenchymal cells enriched in the later disease stages exhibit higher expression of FN1 and stemness-associated genes 64 . Additionally, an independent study found that the interaction between integrins and tumour-deposited fibronectin is involved in the niche-induced cancer cell stemness 65 . The CXCL14 gene encodes a member of the CXC chemokine family whose role in the PDAC is relatively unexplored.…”

Section: Fig 5: Transcriptional Profile Of Triple-high Cells a Umap V...mentioning

confidence: 99%

High-dimensional mass cytometry reveals stemness state heterogeneity in pancreatic ductal adenocarcinoma

Ervin,

Ahern,

Liu

et al. 2024

Preprint

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Stem-like cancer cells harbour high self-renewal capacity, exhibit enhanced tumourigenicity and have been associated with therapy resistance, metastasis and tumour relapse. Therefore, understanding the molecular features of stem-like cells is critical for targeting them effectively and improving treatment outcomes for cancer patients. Several markers have been used to isolate and study the putative stem-like cells of pancreatic ductal adenocarcinoma (PDAC), but the patterns of marker co-expression and overlap between identified individual subpopulations are yet to be comprehensively studied. Here we developed a mass cytometry antibody panel for simultaneous analysis of 33 stemness-associated markers at single-cell resolution. High-dimensional mass cytometry analysis of PDAC cell lines revealed molecularly heterogeneous stemness states and highlighted the role of genotype in determining the cell line-specific stemness signature. Stemness marker expression lie along a continuum in PDAC cell lines and patient samples indicative of stepwise phenotypic transitions. We also identified a subset of PDAC cells co-expressing high levels of Musashi-2, DCLK1 and CXCR4, and harbouring basal-like and EMT transcriptional programmes associated with highly plastic phenotype. This multiplexed analysis uncovers nuance and complexities of the stemness state in the PDAC.

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Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation

Cited by 12 publications

References 54 publications

Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

Canonical Wnt Pathway Is Involved in Chemoresistance and Cell Cycle Arrest Induction in Colon Cancer Cell Line Spheroids

Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept

High-dimensional mass cytometry reveals stemness state heterogeneity in pancreatic ductal adenocarcinoma

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