GLI1‐induced mammary gland tumours are transplantable and maintain major molecular features

Norum, Jens Henrik; Frings, Oliver; Kasper, Maria; Bergholtz, Helga; Thime, H. Zell; Bergström, Åsa; Andersson, Agneta; Kuiper, Raoul V.; Fredlund, Erik; Sørlie, Thérese; Toftgárd, Rune

doi:10.1002/ijc.32522

Cited by 5 publications

(4 citation statements)

References 50 publications

(83 reference statements)

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“…The EMT phenotype in claudin-low tumors may in itself be a therapeutic target, and may also have implications for chemoresistance 37 . Due to the major influence of non-tumor-cell infiltration, it is likely that immunocompetent animal models will be of particular importance for functionally evaluating how these features can be therapeutically targeted 3,13,38,39 .…”

Section: Discussionmentioning

confidence: 99%

Re-definition of claudin-low as a breast cancer phenotype

et al. 2020

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The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors are distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflect characteristics of their intrinsic subtype. Finally, we explore an alternative method for identifying claudin-low tumors and thereby uncover potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.

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Section: Discussionmentioning

confidence: 99%

Re-definition of claudin-low as a breast cancer phenotype

et al. 2020

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“…Functional studies will also be necessary in order to elucidate the etiology of claudin-low breast tumors, and to test novel therapeutic modalities. Due to the major influence of normal cell infiltration, it is likely that immunocompetent animal models will be of particular importance for such studies (3,13,29,30).…”

Section: Discussionmentioning

confidence: 99%

Re-definition of claudin-low as a breast cancer phenotype

Fougner

Bergholtz

Norum

et al. 2019

Preprint

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The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors were distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflected characteristics of their intrinsic subtype. Finally, we have developed an alternative method for identifying claudin-low tumors and thereby uncovered potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.Contact informationC.F. christian.fougner@rr-research.noH.B. helga.bergholtz@rr-research.noJ.H.N. jens.henrik.norum@rr-research.noT.S. therese.sorlie@rr-research.no

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“…SR-3029 displays striking therapeutic efficacy in triple negative as well as HER2 + breast cancer models with WNT involvement [58]. Given the documented oncogenic role of HH-GLI in breast cancer development [75][76][77], it is possible that the therapeutic activity of this CSNK1 inhibitor also relies at least in part on the GLI inhibitory activity described in our study.…”

Section: Discussionmentioning

confidence: 68%

Casein Kinase 1D Encodes a Novel Drug Target in Hedgehog—GLI-Driven Cancers and Tumor-Initiating Cells Resistant to SMO Inhibition

Peer

Aichberger

Vilotic

et al. 2021

Cancers

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(1) Background: Aberrant activation of the hedgehog (HH)—GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH—GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH—GLI-driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity, and monitored the oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO inhibitor-sensitive and -resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent TIC in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor-sensitive and -resistant tumors.

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GLI1‐induced mammary gland tumours are transplantable and maintain major molecular features

Cited by 5 publications

References 50 publications

Re-definition of claudin-low as a breast cancer phenotype

Re-definition of claudin-low as a breast cancer phenotype

Re-definition of claudin-low as a breast cancer phenotype

Casein Kinase 1D Encodes a Novel Drug Target in Hedgehog—GLI-Driven Cancers and Tumor-Initiating Cells Resistant to SMO Inhibition

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