Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics

Iida, Tadashi; Mizutani, Yasuyuki; Esaki, Nobutoshi; Ponik, Suzanne M.; Burkel, Brian; Weng, Liang; Kuwata, Keiko; Masamune, Atsushi; Ishihara, Seiichiro; Haga, Hisashi; Kataoka, Kunio; Mii, Shinji; Shiraki, Yukihiro; Ishikawa, Takuya; Ohno, Eizaburo; Kawashima, Hiroki; Hirooka, Yoshiki; Fujishiro, Mitsuhiro; Takahashi, Masahide; Enomoto, Atsushi

doi:10.1038/s41388-022-02288-9

Cited by 36 publications

(46 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Screening for chemicals capable of promoting conversion of tumour promoting CAFs to rCAF identified the synthetic retinoid Am80 (Tamibarotene) as a promising candidate. Am80 upregulates Meflin expression in stromal cells and enhances gemcitabine chemotherapy response in a subcutaneous mT5 (KPC‐derived PDAC cell line) mouse PDAC model [38], and is now being trialled clinically in combination with gemcitabine and nab‐paclitaxel (Phase I/II; NCT05064618) [39]. Together these diverse studies suggest subpopulations of CAFs can exhibit both tumour‐suppressor and ‐promoter functions at distinct stages of disease development.…”

Section: Conflicting Results From Early Attempts To Target Cafs Thera...mentioning

confidence: 99%

Cancer‐associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets

Kocher

2022

The Journal of Pathology

View full text Add to dashboard Cite

Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting the undesirable properties of CAFs, while attempting to maintain tumour-suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in preclinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma to explore why successful clinical targeting of protumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with a differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF subtyping is the next frontier in understanding and exploiting the tumour microenvironment for therapeutic benefit.

show abstract

Section: Conflicting Results From Early Attempts To Target Cafs Thera...mentioning

confidence: 99%

Cancer‐associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets

Kocher

2022

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Different CAF subpopulations appear to exert tumor-promoting and tumor-restricting functions in PDACs [106,[155][156][157][158][159], indicating the presence of so-called "tumor-promoting CAFs" and "tumor-restricting CAFs". Indeed, preclinical and population-based studies focusing on simple CAF markers, including ACTA2, have obtained conflicting results in the prognostic significance of CAFs in PDACs, although many studies suggested inverse associations between CAF amounts and patient survival time [159][160][161][162][163][164][165][166][167][168].…”

Section: Intertumoral Stromal Heterogeneity and Clinical Implicationsmentioning

confidence: 99%

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

Masugi

2022

Cancers

View full text Add to dashboard Cite

Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.

show abstract

“…Meflin binds with BMP7 to augment its downstream activation of Smad1/5, thereby inducing the expression of inhibitors of DNA binding proteins Id2 and Id3. Another Meflin ligand is lysyl oxidase (Lox), which is a crosslinker of collagen fibers that promotes fibrosis and tissue stiffening [ 43 , 44 , 45 , 46 ]. Our biochemical analysis showed that Meflin interacts with Lox to inhibit its collagen cross-linking activity [ 43 ].…”

Section: Current Understanding About Rcafs In Pdacmentioning

confidence: 99%

“…Another Meflin ligand is lysyl oxidase (Lox), which is a crosslinker of collagen fibers that promotes fibrosis and tissue stiffening [ 43 , 44 , 45 , 46 ]. Our biochemical analysis showed that Meflin interacts with Lox to inhibit its collagen cross-linking activity [ 43 ]. Consistent with this result, the Meflin expression levels in CAFs are anti-correlated with straighter and wider collagen structures in PDAC mouse models.…”

Section: Current Understanding About Rcafs In Pdacmentioning

confidence: 99%

“…Consistent with this result, the Meflin expression levels in CAFs are anti-correlated with straighter and wider collagen structures in PDAC mouse models. Furthermore, Meflin deficiency in CAFs is associated with a more aggressive histology of PDAC and resistance to chemotherapeutics, suggesting that Meflin may be a functional marker of rCAFs in PDAC [ 28 , 43 ]. Our study showed that Meflin exhibits cancer-restraining activity; however, the precise role of Meflin + CAFs has not been demonstrated clearly.…”

Section: Current Understanding About Rcafs In Pdacmentioning

confidence: 99%

See 1 more Smart Citation

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

Ando

Sakai

Iida

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody–drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.

show abstract

Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics

Cited by 36 publications

References 53 publications

Cancer‐associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets

Cancer‐associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

Contact Info

Product

Resources

About