Last update 01 Nov 2024

TGF-β x LRRC15

Last update 01 Nov 2024

Basic Info

Related Targets

TGF-βLRRC15

Drugs associated with TGF-β x LRRC15

LRRC15-antiTGFβR2

Target

LRRC15 x TGF-β

Mechanism

LRRC15 inhibitors [+1]

Active Org.

Bonum Therapeutics, Inc.Startup

Originator Org.

Bonum Therapeutics, Inc.Startup

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TGF-β x LRRC15

100 Translational Medicine associated with TGF-β x LRRC15

0 Patents (Medical) associated with TGF-β x LRRC15

Literatures (Medical) associated with TGF-β x LRRC15

14 Mar 2024·Stem Cells

Leucine-Rich Repeat Containing 15-Mediated Cell Adhesion Is Essential for Integrin Signaling in TGF-β1-Induced PDL Fibroblastic Differentiation

Article

Author: Kim, Hyun-Jin ; Kim, Seong-Min ; Jang, Young-Joo ; Kim, Dong-Jun

AbstractHuman periodontal ligament cells (hPDLCs) cultured from periodontal ligament (PDL) tissue contain postnatal stem cells that can be differentiated into PDL fibroblasts. We obtained PDL fibroblasts from hPDLCs by treatment with low concentrations of TGF-β1. Since the extracellular matrix and cell surface molecules play an important role in differentiation, we had previously developed a series of monoclonal antibodies against PDL fibroblast-specific cell surface molecules. One of these, the anti-PDL51 antibody, recognized a protein that was significantly upregulated in TGF-β1-induced PDL fibroblasts and highly accumulated in the PDL region of the tooth root. Mass spectrometry revealed that the antigen recognized by the anti-PDL51 antibody was leucine-rich repeat containing 15 (LRRC15), and this antibody specifically recognized the extracellular glycosylated moiety of LRRC15. Experiments presented here show that as fibroblastic differentiation progresses, increased amounts of LRRC15 localized at the cell surface and membrane. Inhibition of LRRC15 by siRNA-mediated depletion and by antibody blocking resulted in downregulation of the representative PDL fibroblastic markers. Moreover, following LRRC15 inhibition, the directed and elongated cell phenotypes disappeared, and the long processes of the end of the cell body were no longer found. Through a specific interaction between integrin β1 and LRRC15, the focal adhesion kinase signaling pathway was activated in PDL fibroblasts. Furthermore, it was shown that increased LRRC15 was important for the activation of the integrin-mediated cell adhesion signal pathway for regulation of cellular functions, including fibroblastic differentiation, proliferation, and cell migration arising from the expression of PDL-related genes in TGF-β1-induced PDL fibroblastic differentiation.

03 Nov 2022·NatureQ1 · CROSS-FIELD

LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity

Q1 · CROSS-FIELD

Article

Author: Gandham, Vineela ; Nabet, Barzin Y ; Mariathasan, Sanjeev ; Chalouni, Cécile ; Mao, Weiguang ; Breart, Beatrice ; Modrusan, Zora ; Sanchez, Patricia L ; Thai, Minh ; Turley, Shannon J ; Roose-Girma, Merone ; Ziai, James ; Elstrott, Justin ; Yang, Yeqing Angela ; Buechler, Matthew B ; Pillow, Thomas H ; Bacarro, Natasha ; Sadowsky, Jack ; Müller, Sören ; Lewis, Gail D ; Rowntree, Rebecca K ; Banchereau, Romain ; Tam, Lucinda ; Dunlap, Debra ; Qu, Yan ; Pradhan, Rachana N ; Caothien, Roger ; Zacharias, Neelie ; Krishnamurty, Akshay T ; Shyer, Justin A ; Wang, Amber W

AbstractRecent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1–3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.

01 Feb 2021·Pediatric Blood & CancerQ3 · MEDICINE

LRRC15 antibody‐drug conjugates show promise as osteosarcoma therapeutics in preclinical studies

Q3 · MEDICINE

Article

Author: Helman, Lee J. ; Slemmons, Katherine K. ; Purcell, James W. ; Mukherjee, Sanjit ; Meltzer, Paul

AbstractBackgroundOsteosarcoma (OS), the most common bone tumor in children and adolescents, has high rates of metastasis leading to poor survival. Leucine‐rich repeat containing 15 (LRRC15), a transmembrane protein whose expression is modulated by TGFβ, was recently shown to be highly expressed on the surface of OS tumor cells. Here, we evaluate a novel antibody‐drug conjugate (ADC) targeting LRRC15 in OS human cell lines and murine xenografts. We compare this new ADC, which is conjugated to the anthracycline derivative PNU‐159682 (PNU), to a previously studied LRRC15 ADC that is conjugated to the tubulin inhibitor monomethyl auristatin E (MMAE), since anthracyclines are standard of care in OS.ProcedureWe evaluated LRRC15 expression in OS cells using Western blots and flow cytometry, and analyzed the epigenetic landscape of the LRRC15 locus using chromatin immunoprecipitation. Efficacy of ADCs on cell growth was analyzed by IncuCyte live cell imaging. Intramuscular xenograft tumor growth was assessed by bioluminescence imaging and hematoxylin and eosin staining.ResultsLRRC15‐PNU is more effective at inhibiting growth in vitro and in vivo than an isotype antibody control or the LRRC15‐MMAE ADC in two high LRRC15 expressing OS cell lines. Low expressing cell lines are not sensitive to either ADC. Importantly, cells with low LRRC15 expression are amenable to re‐expression after TGFβ treatment, suggesting a potential to sensitize insensitive OS cells to LRRC15 ADC treatment. In vivo, LRRC15‐PNU had cure rates of 40‐100% in OS xenograft models.ConclusionsOverall, LRRC15‐directed ADCs are a promising new avenue for OS treatment.

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