Targeting Cancer‐Associated Fibroblasts: Eliminate or Reprogram? DOI Creative Commons
Masaya Yamazaki, Takatsugu Ishimoto

Cancer Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

ABSTRACT Cancer‐associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in progression and treatment resistance, CAFs promising therapeutic targets cancer. The elimination tumor‐promoting has been investigated animal models to determine whether it effectively suppresses growth. Based on recent evidence, several simple strategies have proposed eliminate attenuate these features. In addition, attention focused critical role that play immunosuppressive TME. Therefore, functional reprogramming combination with immune checkpoint inhibitors also as a possible approach. However, although potential widely characterized, plasticity heterogeneity complicate understanding properties present difficulties for clinical application. Moreover, identification tumor‐suppressive highlights necessity development approaches can distinguish switch between an appropriate manner. this review, we introduce origins diversity CAFs, cancer, current aimed at targeting including ongoing evaluations.

Language: Английский

Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics? DOI
Mamta Singh, Julieta Afonso, Dolly Sharma

et al.

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 90, P. 1 - 14

Published: Jan. 24, 2023

Language: Английский

Citations

59
Barriers to immune cell infiltration in tumors DOI Creative Commons
Marit M. Melssen, Natasha D. Sheybani,

Katie M. Leick

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(4), P. e006401 - e006401

Published: April 1, 2023

Increased immune cell infiltration into tumors is associated with improved patient survival and predicts response to therapies. Thus, identification of factors that determine the extent crucial, so methods intervene on these targets can be developed. T cells enter tumor tissues through vasculature, under control interactions between homing receptors receptor ligands (HRLs) expressed by vascular endothelium nests. HRLs are often deficient in tumors, there also may active barriers infiltration. These remain understudied but crucial for enhancing immune-mediated cancer control. Multiple intratumoral systemic therapeutic approaches show promise enhance infiltration, including both approved therapies experimental This review highlights intracellular extracellular determinants intervention

Language: Английский

Citations

59
Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer DOI Creative Commons
Christopher J. Hanley, Sara Waise, Matthew Ellis

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 31, 2023

Abstract Fibroblasts are poorly characterised cells that variably impact tumour progression. Here, we use single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry (CIBERSORTx) to identify characterise three major fibroblast subpopulations in human non-small lung cancer: adventitial, alveolar myofibroblasts. Alveolar adventitial fibroblasts (enriched control tissue samples) localise discrete spatial niches histologically normal indicate improved overall survival rates when present adenocarcinomas (LUAD). Trajectory inference identifies phases of activation, leading myofibroblast enrichment samples: initial upregulation inflammatory cytokines, followed by stress-response signalling ultimately increased expression fibrillar collagens. Myofibroblasts correlate with poor LUAD, associated loss epithelial differentiation, TP53 mutations, proximal molecular subtypes myeloid recruitment. In squamous carcinomas myofibroblasts were not prognostic despite being transcriptomically equivalent. These findings have important implications for developing fibroblast-targeting strategies cancer therapy.

Language: Английский

Citations

55
Colorectal Cancer Organoid–Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses DOI Creative Commons
Henner F. Farin, Mohammed H. Mosa, Benardina Ndreshkjana

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(10), P. 2192 - 2211

Published: July 25, 2023

In colorectal cancers, the tumor microenvironment plays a key role in prognosis and therapy efficacy. Patient-derived organoids (PDTO) show enormous potential for preclinical testing; however, cultured cells lose important characteristics, including consensus molecular subtypes (CMS). To better reflect cellular heterogeneity, we established cancer organoid-stroma biobank of matched PDTOs cancer-associated fibroblasts (CAF) from 30 patients. Context-specific phenotyping showed that xenotransplantation or coculture with CAFs improves transcriptomic fidelity instructs subtype-specific stromal gene expression. Furthermore, functional profiling exposed CMS4-specific therapeutic resistance to gefitinib SN-38 prognostic expression signatures. Chemogenomic library screening identified patient- therapy-dependent mechanisms MET as common target. Our results demonstrate phenotypes are encrypted epithelium plastic fashion strongly depends on context. Consequently, essential faithful representation responses ex vivo. Systematic characterization provides resource context dependency cancer. We subtype memory is independent specific driver mutations. data underscore importance cocultures improved testing identification mechanisms. This article featured Selected Articles Issue, p. 2109.

Language: Английский

Citations

53
First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial DOI Creative Commons
Marion Thibaudin, Jean-David Fumet, Benoist Chibaudel

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 2087 - 2098

Published: Aug. 1, 2023

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy targeted therapies remains the only therapeutic option for stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated safety and efficacy of durvalumab plus tremelimumab combined mFOLFOX6 in first line, 57 RAS-mutant unresectable CRC. Safety was primary objective Ib; no issue observed. 2 terms 3-month progression-free survival (PFS) MSS tumors met, PFS 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate 64.5%; median 8.2 months CI: 5.9-8.6); overall not reached We observed higher tumor mutational burden lower genomic instability responders. Integrated transcriptomic analysis underlined that high signature low epithelial-mesenchymal transition were associated better outcome. Immunomonitoring showed induction neoantigen NY-ESO1 TERT blood tumor-specific T cell PFS. combination durvalumab-tremelimumab tolerable promising clinical activity mCRC. Clinicaltrials.gov identifier: NCT03202758 .

Language: Английский

Citations

46
Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution DOI Creative Commons
Federica Francescangeli, Maria Laura De Angelis, Rachele Rossi

et al.

Cancer and Metastasis Reviews, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 9, 2023

Abstract The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure current treatment protocols. In rapidly evolving scenario growing tumor, anticancer treatments impose drastic perturbation not only to cells but also tumor microenvironment, killing portion and inducing massive stress response survivors. Consequently, can act as double-edged sword by temporary while laying ground for therapy resistance subsequent disease progression. Cancer cell dormancy (or quiescence) is central theme evolution, being tightly linked tumor’s ability survive cytotoxic challenges, metastasize, resist immune-mediated attack. Accordingly, quiescent (QCCs) have been detected virtually all stages development. recent years, an increasing number studies focused on characterization quiescent/therapy resistant cells, unveiling QCCs core transcriptional programs, metabolic plasticity, mechanisms immune escape. At same time, our partial understanding quiescence reflects difficulty identify stable biomarkers/therapeutic targets control settings. This review focuses discoveries interrelated fields dormancy, stemness, resistance, discussing experimental evidences frame nonlinear dynamics approach, exploring possibility that may represent peril potential therapeutic resource.

Language: Английский

Citations

43
Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer DOI Creative Commons
Hugo Croizer, Rana Mhaidly, Yann Kieffer

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 1, 2024

Abstract Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute transcriptomics at single-cell level perform functional assays to generate a high-resolution integrated map cancer (BC), with focus on inflammatory myofibroblastic (iCAF/myCAF) CAF clusters. We identify 10 spatially-organized CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent organization, cells drive the transition detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via DPP4- YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK T induce while Detox-iCAF associated FOLR2+ macrophages an immuno-protective EcoCellType. subpopulations accumulate differently according invasive BC status predict recurrence ductal carcinoma situ (DCIS), could help identifying low-risk DCIS patients eligible for therapeutic de-escalation.

Language: Английский

Citations

32
Mechanisms of metastatic colorectal cancer DOI
Adrià Cañellas‐Socias, Elena Sancho, Eduard Batlle

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(9), P. 609 - 625

Published: May 28, 2024

Language: Английский

Citations

30
Cancer stem cell mimicry for immune evasion and therapeutic resistance DOI
Phei Er Saw, Qiang Liu, Ping‐Pui Wong

et al.

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(8), P. 1101 - 1112

Published: June 25, 2024

Language: Английский

Citations

30
Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy DOI Creative Commons

Tianchen Guo,

Junfen Xu

Cancer and Metastasis Reviews, Journal Year: 2024, Volume and Issue: 43(3), P. 1095 - 1116

Published: April 11, 2024

Abstract Tumor microenvironment (TME) has been demonstrated to play a significant role in tumor initiation, progression, and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of TME exhibit heterogeneous properties their communication with cells. This heterogeneity CAFs can be attributed various origins, including quiescent fibroblasts, mesenchymal stem cells (MSCs), adipocytes, pericytes, endothelial cells, mesothelial Moreover, single-cell RNA sequencing identified diverse phenotypes CAFs, myofibroblastic (myCAFs) inflammatory (iCAFs) being most acknowledged, alongside newly discovered subtypes like antigen-presenting (apCAFs). Due these heterogeneities, exert multiple functions tumorigenesis, cancer stemness, angiogenesis, immunosuppression, metabolism, As result, targeted therapies aimed at TME, particularly focusing on rapidly developing, fueling promising future advanced tumor-targeted therapy.

Language: Английский

Citations

29