LRRC15: A Stromal Target in Cancer and Fibrosis

• Gene Information: LRRC15 is a transmembrane protein of the leucine-rich repeat (LRR) family located on chromosome 3q29. It functions as a stromal regulator involved in tumor progression, tissue remodeling, and fibrosis.
• Protein Expression: LRRC15 is minimally expressed in normal tissues but is highly induced in cancer-associated fibroblasts (CAFs), activated fibroblasts, and fibrotic tissues. It is highly enriched in the stroma of multiple solid tumors and is associated with an immunosuppressive tumor microenvironment.
• Signaling Pathway: LRRC15 is closely associated with TGF-β-driven stromal activation. LRRC15-positive fibroblasts promote extracellular matrix remodeling, collagen deposition, fibrosis, and immune exclusion, contributing to tumor progression and stromal remodeling.
• Therapeutic Intervention: Due to its selective expression in tumor stroma, LRRC15 has emerged as a promising therapeutic target. Approaches including ADCs and monoclonal antibodies aim to remodel the tumor microenvironment, reduce fibrosis, enhance immune infiltration, and improve anti-tumor efficacy.

LRRC15

• Exon 2 of mouse Lrrc15 gene that encode part of extracellular domain is replaced by human counterparts in B-hLRRC15 mice.
• The genomic region of mouse Lrrc15 gene that encodes signal peptide, transmembrane domain and cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. The chimeric LRRC15 expression is driven by endogenous mouse Lrrc15 promoter, while mouse Lrrc15 gene transcription and translation will be disrupted.

• Human LRRC15 is specifically and correctly expressed in B-hLRRC15 mice.

Human LRRC15 was detectable in B-hLRRC15 mice by RT-PCR and sequencing. Brain tissues were isolated from wild-type C57BL/6 mice (+/+) and homozygous B-hLRRC15 mice (H/H). (A) Primers were designed to detect human LRRC15 and mouse LRRC15. (B) Human LRRC15 mRNA was detectable in B-hLRRC15 mice, but not in wild-type mice. Sequencing of PCR products confirmed that the amplified sequences were consistent with database reference sequences.

• LRRC15 protein expression was detected in the skin of wild-type mice and homozygous B-hLRRC15 mice, as the antibody's cross-reactivity with both human and mouse species.
• LRRC15 protein was detected only in the small intestine of wild-type mice.

Immunohistochemical analysis of organs in B-hLRRC15 mice. Major organs were collected from wild-type C57BL/6 mice and homozygous B-hLRRC15 mice (female, 6-7-week-old), and analyzed by IHC using anti-LRRC15 antibody (CST, #50546S). The arrow indicates tissue cells with positive LRRC15 staining (brown). “+” indicates that the tissue is positive, and “-” indicates that the tissue is negative.

• Human LRRC15 protein is detectable in the tumor stromal cells of B-hLRRC15 mice inoculated with LCC1, Pan02, and E0771.

Immunohistochemical (IHC) analysis of human LRRC15 expression in tumors from B-hLRRC15 mice bearing PAN02, LLC1, and E0771 cell-derived grafts. Tumors were collected from B-hLRRC15 mice at the experimental endpoint, and analyzed by IHC using anti-LRRC15 antibody (provided by the client).

Notes: This data was validated collaboratively by the client and Biocytogen (24P095803).

Establishment of a PAN02 model and in vivo efficacy study of a LRRC15-targeting ADC. PAN02 pancreatic cancer cells were implanted subcutaneously into homozygous B-hLRRC15 mice (female, 6 weeks old, n = 8). When the average tumor volume reached approximately 203 mm³, mice were randomized and subsequently administered the LRRC15-targeting ADC (provided by the client).

Notes: This data was validated collaboratively by the client and Biocytogen.

Efficacy of a LRRC15-targeting ADC in B-hLRRC15 mice. (A) Tumor growth curves. (B) Body weight changes during treatment. As shown in panel A, the LRRC15-targeting ADC (provided by the client) was efficacious in controlling tumor growth in B-hLRRC15 mice in a dose-dependent manner, demonstrating that the B-hLRRC15 mice provide a powerful preclinical model for in vivo evaluation of LRRC15-targeting ADC . Values are expressed as mean ± SEM.

Notes: This data was validated collaboratively by the client and Biocytogen.