Biology subjects

Larkeryd, A.

Publications and source records attributed to Larkeryd, A..

3 recordsLinked to original sources

bioRxiv2026

Spatially-resolved multimodal profiling identifies functionally-heterogeneous cancer-associated fibroblasts associated with poor radiotherapy outcomes in muscle-invasive bladder cancer.

Background: Cancer-associated fibroblasts (CAFs) contribute to systemic therapy resistance in muscle-invasive bladder cancer (MIBC), but their functional heterogeneity and relevance to curative bladder-preserving radiotherapy, are poorly understood. Methods: Transcriptomic analysis was performed on 279 tumours from BC2001, a phase 3 radiotherapy clinical trial. To study CAF heterogeneity, we integrated bulk RNA-seq, single-cell spatial analysis of multiplex immunofluorescence images and quantification of extracellular matrix (ECM) features in 155 MIBC biopsies. The functional heterogeneity of distinct CAF populations was evaluated by single-nuclear RNA-seq. Spatial interactions between CAF populations and CD8+ T-cells was assessed and the relevance of lymphocytes to radiation responses was evaluated in a CAF-enriched murine bladder cancer model (BBN963). Results: BC2001 patients with CAF-enriched tumours had worse overall survival (HR=1.671, 95% CI 1.221-2.287, Log-rank p=0.0012). CAF abundance and antigen expression was highly heterogenous. Podoplanin (PDPN) was expressed on the majority of CAFs and was associated with inflammatory pathways. Enrichment of CAF gene signatures was associated with a significant increase in CAFs expressing fibroblast activation protein (FAP) (p=0.004) and dense ECM features (p=0.0004). Fifty-three percent of tumours exhibited stromal CD8+ T-cell exclusion with significant enrichment in FAP-dominant neighbourhoods (p<0.001). In vivo, lymphocytes were critical for radiation-induced tumour control, indicating that immune cold or excluded tumours may have limited radiotherapy responses. Conclusion: In MIBC, CAFs are associated with poor radiotherapy outcomes. Multiple mechanisms are deployed by functionally-heterogeneous CAFs, including promotion of chronic inflammation by PDPN+ CAFs and ECM remodelling by FAP+ CAFs which impact CD8+ T-cell distribution and radiation responses.

cancer biology↗

bioRxiv2026

Collagen targeting IL-12 combined with Doxorubicin enhances the anti-tumor effect against osteosarcoma

Osteosarcoma (OS) is the most prevalent primary bone malignancy in children and adolescents; however, therapeutic outcomes remain suboptimal due to tumor heterogeneity, chemoresistance, and inadequate immune activation. Doxorubicin (Dox), the standard therapy that induces immunogenic cell death, has its efficacy compromised by the immunosuppressive tumor microenvironment (TME). While interleukin-12 (IL-12) can activate and recruit various immune cells, making it an attractive combination partner, its systemic delivery is severely limited by dose-limiting toxicity. We have previously reported that intravenous injection of A3 collagen binding domain (CBD) of von Willebrand Factor preferentially accumulates into the TME of various tumor models enriched in collagen I and III. Furthermore, CBD-fused IL-12 (CBD-IL-12) demonstrated superior therapeutic effects against various cancer models compared to unmodified IL-12 due to its collagen-targeted delivery and the resulting tumor-localized inflammation. Given that the OS TME also exhibits higher collagen I and III expression compared to normal bone, we hypothesized that a CBD-IL-12 fusion protein could showcase potent anti-tumor efficacy in OS via tumor-specific accumulation. Here, we demonstrated that CBD-IL-12 exhibited 4-fold enhanced tumor accumulation compared to unmodified IL-12 and increased cytotoxic T cell infiltration by 2.2-fold within the immune-cold microenvironment in a mouse model of OS. The combination of CBD-IL-12 with Dox significantly prolonged median survival in two independent murine OS models. This coordinated approach utilizing Dox coupled with precision-targeted IL-12 immunotherapy represents a clinically translatable strategy that overcomes the inherent limitations of single-agent treatments for OS. HighlightO_LICollagen-targeted IL-12 increases tumor accumulation in osteosarcoma. C_LIO_LIThe collagen-targeted IL-12 synergizes with doxorubicin in osteosarcoma models. C_LIO_LICombination therapy enhances T cell differentiation and activates innate immunity. C_LI

bioengineering↗

bioRxiv2025

Distinct druggable biological processes in early-onset prostate cancer

Despite advances in understanding and treating Prostate Cancer (PCa), there has been little effort to systematically map the biology distinguishing Early-(EOPCa) and Late-(LOPCa) onset PCa. Around 25% of EOPCa cases present with metastatic spread or aggressive disease with earlier metastatic development. Some available lines of therapy are extending treatment trajectories and prolonging lives. However, there remains a critical clinical need to identify new therapeutic targets for EOPCa where life expectancy necessitates safer, more targeted treatment options. To our knowledge, here we present the largest systematic analysis of molecular profiles in EOPCa versus LOPCa, employing machine-learning-enabled algorithms to identify distinguishing biology and druggable targets for each age group. Distinct stromal signatures are uncovered in EOPCa, which are used to propose therapeutic opportunities herein. Moreover, our analysis identifies 50 druggable targets, 11 of which we confirm in PCa cell line genetic/pharmacological perturbation data. These findings provide the first specific, testable hypotheses in EOPCa, offering avenues for experimental validation and potential therapeutic exploitation, and, more generally, shed light on the intricate and distinguished molecular profile of this aggressive, poorly understood disease. One Sentence SummaryMachine learning-enabled algorithms were utilized to identify distinguishing biology and associated druggable targets for early-onset prostate cancers.

cancer biology↗