Therapeutic Progress Research Articles

Visionary Health Architects and Leaders: The Strategic Role of Medical Advisors in Modern Pharma.

This paper reviews the pivotal role of the Medical Advisor (MA) within the medical department of the pharmaceutical industry, highlighting their essential contribution to the development, commercialization, and appropriate use of medicines. In an environment characterised by stringent regulations and increasing demands for transparency, the MA role has become an indispensable position for ensuring optimal integration between scientific innovation and commercial strategy. The work of MAs facilitates cross-functional collaboration between a board spectrum of internal teams and external stakeholders, ensuring that scientific and clinical knowledge is effectively integrated at every stage of the product lifecycle. This includes leveraging emerging new technologies such as artificial intelligence and digital health solutions, as well as using machine learning to enhance predictive analytics. Such integration is critical to addressing unmet medical needs while aligning these initiatives with broader business objectives to drive innovation, market competitiveness, and patient outcomes. We explore the key responsibilities of today's MAs, which include contributing to the generation of data through clinical trials and post-authorization studies, providing continuing medical education, and communicating accurate information to diverse audiences, including healthcare providers, regulators, and patients. Furthermore, MAs promote innovation and therapeutic progress, acting as guardians of medical ethics. This review aims to provide a comprehensive understanding of the strategic role of MAs in bridging the gap between scientific research and clinical practice. Their contributions are critical to addressing current industry challenges, ensuring that companies remain competitive and making a significant contribution to patient wellbeing and medical progress.

Abstract A025: Direct in vivo CRISPR screen identifies BAP1 and FAT1 as potent tumor suppressors in sarcomagenesis

Abstract Undifferentiated pleomorphic sarcoma (UPS) is among the most common soft tissue sarcomas (STS) in adults. For decades, little therapeutic progress has been made for STSs, including UPSs. Targeted therapies for tumors driven by specific genetic mutations have proven to be more effective than standard chemotherapies. However, the molecular pathogenesis of UPSs remains unknown, hindering the development of targeted therapies for UPSs. Approximately 65% of UPSs harbor TP53 mutations, but somatic mutation of Trp53 alone is insufficient to induce sarcomas in vivo. The addition of Rb1 mutation alongside a Trp53 mutation induces sarcomas in vivo, though with low frequency of tumor onset and slow growth. The role of other genes in facilitating Trp53-driven sarcomas is largely unknown. Through a customized in vivo CRISPR/Cas9 screen of 35 genes commonly mutated in UPSs, followed by individual gene validation in vivo, we discovered that Bap1 knockout cooperates with Trp53 knockout to induce sarcomas in vivo. Furthermore, we demonstrated that Fat1 deletion increased the onset frequency and growth of Trp53 and Rb1-driven sarcomas in a genetically engineered mouse model. Through multiplex immunohistochemistry and flow cytometry, we found that mouse sarcomas induced by Trp53 and Rb1 mutations are significantly enriched with immune cells compared to other mouse sarcomas we generated in vivo. Finally, we show that PARP inhibition may be a potential targeted therapy for RB1-loss STSs and BRD4 inhibition may be a potential targeted therapy for FAT1-loss STSs. Citation Format: Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Andrea R Daniel, Zhaoyu Sun, Nerissa T Williams, Melissa J Kasiewicz, Yaping Wu, Diana M Cardona, Brian Piening, John T. Welle, Wesley K Rosales, Venkatesh Rajamanickam, So Young Kim, Eric Xu, Lixia Luo, Yan Ma, Kristianne M Oristian, Omar Lopez, Nicholas E. S. Sibinga, Rutulkumar Patel, Ziqiang Zhang, Alexander J Lazar, Corinne M Linardic, Brady Bernard, William L Redmond, Walter J Urba, David G Kirsch. Direct in vivo CRISPR screen identifies BAP1 and FAT1 as potent tumor suppressors in sarcomagenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A025.

Clinical Translation of Hyperpolarized 13C Metabolic Probes for Glioma Imaging.

Hyperpolarized carbon-13 (HP-13C) MRI enables the real-time measurement of dynamic metabolism by utilizing molecular probes whose magnetization has been transiently enhanced via dynamic nuclear polarization of 13C labels. Based on pre-clinical and clinical investigations demonstrating Warburg-related metabolic dysfunction and tricarboxylic acid (TCA)-cycle alterations in gliomas, HP13C techniques appear very promising for overcoming conventional challenges to evaluating tumor burden and extent, early therapeutic response and progression among patients non-invasively. This article surveys the multi-faceted translational development of HP-13C MRI in the context of glioma imaging, while emphasizing innovation concerning the pharmacy production of HP probes - [1-13C]/[2-13C]-pyruvate and [1-13C,5-12C]-alpha-ketoglutarate - that serve as non-radioactive metabolic contrast agents. Borrowing from practical experience, we present specific probe indications for isocitrate dehydrogenase (IDH)-wildtype glioblastomas and IDH-mutant gliomas together with example data to show the targeted, pathway-dependent function of these agents and their utility. Additional information pertaining to HP-13C hardware, acquisition and post-processing techniques provides an overview of the imaging methodology as it is currently performed at a leading institution. Considering the developing markers for progressive disease in glioblastomas and rapidly advancing capability, this unique imaging technology appears poised for translational impact following further evaluation.ABBREVIATIONS: 2-HG = D-2-hydroxyglutarate; α-KG = alpha-ketoglutarate; CSI = chemical shift imaging; d-DNP = dissolution-dynamic nuclear polarization; EPI = echo-planar imaging; EPSI = echo-planar spectroscopic imaging; IDHm = isocitrate dehydrogenasemutant; IR-SPGR = inversion recovery-prepared fast spoiled gradient-recalled (imaging); LrGGs = lower-grade gliomas; NMR = nuclear magnetic resonance; OGC = oxoglutarate carrier; PHIP = parahydrogen-induced polarization; SNR = signal-to-noise ratio; TCA cycle = tricarboxylic acid cycle; WHO = World Health Organization.

Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics.

Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics.

Topical Administration of Nanostructured Lipid Carriers as a Viable Approach to Reduce Inflammation: A Review.

This review seeks to assess the potential of nanomaterials, specifically Nano-struc-tured Lipid Carriers (NLCs), in mitigating challenges associated with inflammation-related disorders, with a particular emphasis on chronic ailments like arthritis. A comprehensive lit-erature review spanning Web of Science, PubMed, and other scholarly repositories from 2000 to 2023 is conducted. Articles are selected based on their focus on NLCs and inflammation management, utilizing keywords, such as "nanomaterials," "targeted drug delivery," and "ar-thritis." Exclusion criteria involve non-English studies or those lacking adequate detail on NLCs. Synthesized data provide an overview of the advantages, challenges, and prospects of NLCs in addressing chronic inflammatory disorders. This review also examines the therapeu-tic applications of nanotechnology, including targeted drug delivery and tissue engineering, particularly focusing on the intricate biological responses in chronic inflammation, often in-volving Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Moreover, the exploration ex-tends to topical delivery methods to enhance control over medication concentration, with a review of lipid nanoparticles, such as liposomes and solid-lipid nanoparticles, highlighting their potential in augmenting drug permeation while addressing challenges like inadequate drug loading. NLCs have emerged as promising candidates for overcoming drug delivery challenges, par-ticularly in arthritis treatment, with a focus on their advantages across diverse lipid composi-tions. The review underscores significant strides in inflammation management through NLC utilization, offering insights into future research directions. Moreover, it contributes to ongoing advancements in nanomedicine, emphasizing the pivotal role of NLCs in developing innovative therapeutic approaches for inflammation-related dis-orders, particularly arthritis. NLCs represent a promising avenue for effective interventions, signaling progress in nanotechnology-enabled therapeutics.

FABP5 is a key player in metabolic modulation and NF-κB dependent inflammation driving pleural mesothelioma

Pleural mesothelioma (PM) poses a significant challenge in oncology due to its intricate molecular and metabolic landscape, chronic inflammation, and heightened oxidative stress, which contribute to its notorious resilience and clinical complexities. Despite advancements, the precise mechanisms driving PM carcinogenesis remain elusive, impeding therapeutic progress. Here, we explore the interplay between tumor growth dynamics, lipid metabolism, and NF-κB dysregulation in malignant pleural mesothelioma, shedding light on novel molecular mechanisms underlying its pathogenesis. Our study reveals distinctive growth dynamics in PM cells, characterized by heightened proliferation, altered cell cycle progression, and resistance to apoptosis. Intriguingly, PM cells exhibit increased intracellular accumulation of myristic, palmitic, and stearic acids, suggestive of augmented lipid uptake and altered biosynthesis. Notably, we identify FABP5 as a key player in driving metabolic alterations and inflammation through NF-κB dysregulation in mesothelioma cells, distinguishing them from normal mesothelial cells. Silencing of FABP5 leads to significant alterations in cell dynamics, metabolism, and NF-κB activity, highlighting its potential as a therapeutic target. Our findings unveil a reciprocal relationship between lipid metabolism and inflammation in PM, providing a foundation for targeted therapeutic strategies. Overall, this comprehensive investigation offers insights into the intricate molecular mechanisms driving PM pathogenesis and identifies potential avenues for therapeutic intervention.

Long-term patient-reported outcomes following allogeneic hematopoietic cell transplantation.

Therapeutic progress has improved the overall survival of patients treated with allogeneic hematopoietic cell transplantation (alloHCT). Thus, the impact on quality of life (QoL) becomes increasingly relevant. However, QoL is not monitored regularly in clinical practice, and most trials stop QoL assessments early post-alloHCT, missing long-term dynamics. To address this knowledge gap, we conducted a cross-sectional survey of 214 adult alloHCT recipients (average age 53 y, 42.5% female, median follow-up 56 months) to evaluate QoL using patient-reported outcome measurements (PROMs), spanning a period from 30 days to over 10 years post-transplant. Participants completed the EORTC QLQ-C30 and FACT-BMT at a single follow-up timepoint to investigate QoL-related factors. Comparing long-term follow-up patients (beyond year 3, n = 125) with short-term follow-up patients (day 30 to month 12, n = 89) shows significantly better long-term QoL outcomes (P = 0.016). However, PROM symptom scales indicate moderate fatigue and insomnia rates in long-term survivors. Better QoL was associated with male gender, lower ECOG, RIC conditioning, no relapse, no ongoing immunosuppression and full-time work. Summarized, while we observe encouraging long-term outcomes, our data suggest that QoL recovery remain highly individual. We strongly recommend the use of PROMs to enhance our understanding of long-term survivorship post-alloHCT.

Stem Cell Perspective for Regenerative Wound Healing: from Biology toward Future Clinical Directions: A Review.

Chronic wounds, a major clinical challenge, still need to develop new methods based on efficient technologies to improve treatment results. Stem cells, particularly mesenchymal stem cells (MSC), as an advanced approach in skin regenerative medicine, brought new hopes. The multifaceted effects of MSCs, including paracrine signaling, trophic factor secretion, and modulation of the wound microenvironment, orchestrate a cascade of regenerative, plays a critical role in tissue repair. Preclinical investigations have revealed the regenerative capacity of MSCs in accelerating wound closure, promoting angiogenesis, and fostering a pro-healing environment in chronic wound models. Clinical trials have also confirmed these findings and show the efficacy of MSC treatment in accelerating wound healing and improving the quality of healed tissue in patients with chronic wounds. Despite the therapeutic progress, key issues, such as optimal cell sourcing, cell dosage, delivery modalities, and long-term safety profiles, there are a number of unresolved issues which need to be dealt with. This review aims to provide a comprehensive overview of current state of stem cell research in wound healing, and offers a new new hope for effective and innovative treatments in regenerative medicine.

A hybrid inception-dilated-ResNet architecture for deep learning-based prediction of COVID-19 severity

Chest computed tomography (CT) scans are essential for accurately assessing the severity of the novel Coronavirus (COVID-19), facilitating appropriate therapeutic interventions and monitoring disease progression. However, determining COVID-19 severity requires a radiologist with significant expertise. This study introduces a pioneering utilization of deep learning (DL) for evaluate COVID-19 severity using lung CT images, presenting a novel and effective method for assessing the severity of pulmonary manifestations in COVID-19 patients. Inception-Residual networks (Inception-ResNet), advanced hybrid models known for their compactness and effectiveness, were used to extract relevant features from CT scans. Inception-ResNet incorporates the dilated mechanism into its ResNet component, enhancing its ability to accurately classify lung involvement stages. This study demonstrates that dilated residual networks (dResNet) outperform their non-dilated counterparts in image classification tasks, as their architectural designs allow the systems to acquire comprehensive global data by expanding their receptive fields. Our study utilized an initial dataset of 1548 human thoracic CT scans, meticulously annotated by two experienced specialists. Lung involvement was determined by calculating a percentage based on observations made at each scan. The hybrid methodology successfully distinguished the ten distinct severity levels associated with COVID-19, achieving a maximum accuracy of 96.40%. This system demonstrates its effectiveness as a diagnostic framework for assessing lung involvement in COVID-19-affected individuals, facilitating disease progression tracking.

A Versatile Strategy to Transform Cationic Polymers for Efficient and Organ‐Selective mRNA Delivery

AbstractThe progress of mRNA therapeutics underscores the imperative demand for the development of targeted delivery systems. While cationic polymers hold promise as genetic vectors, their poor in vivo efficacy and numerous variants highlight the urgent need for a universal functionalization strategy to bolster their delivery capabilities. Here, we present a versatile strategy to transform low‐cost commercial cationic polymers into phospholipidated and alkylated polymers (PAPs), enabling efficient and organ‐selective mRNA delivery in vivo. This straightforward post‐functionalization method can be readily broadened to a diverse array of existing cationic polymers, enhancing their cellular uptake, endosomal escape, and mRNA release functionalities. Consequently, PAPs facilitate up to 30,500‐fold higher mRNA expression compared to their unmodified counterparts in vivo. Notably, the one‐component PAPs enable spleen‐specific mRNA delivery, with their vaccine application validated in a mouse melanoma model following intravenous administration. Better still, PAPs can synergize with different helper lipids to formulate four‐component lipid nanoparticles (LNPs), achieving respective lung‐ and liver‐specific mRNA delivery. Noteworthy is that these organ‐selective mRNA delivery systems significantly outperform previous polymer and LNP benchmarks. This transformation strategy for cationic polymers represents a generalized methodology to give highly effective mRNA carriers, highlighting substantial potential for clinical translation of mRNA therapies with organ‐targeting requirements.

A Versatile Strategy to Transform Cationic Polymers for Efficient and Organ-Selective mRNA Delivery.

The progress of mRNA therapeutics underscores the imperative demand for the development of targeted delivery systems. While cationic polymers hold promise as genetic vectors, their poor in vivo efficacy and numerous variants highlight the urgent need for a universal functionalization strategy to bolster their delivery capabilities. Here, we present a versatile strategy to transform low-cost commercial cationic polymers into phospholipidated and alkylated polymers (PAPs), enabling efficient and organ-selective mRNA delivery in vivo. This straightforward post-functionalization method can be readily broadened to a diverse array of existing cationic polymers, enhancing their cellular uptake, endosomal escape, and mRNA release functionalities. Consequently, PAPs facilitate up to 30,500-fold higher mRNA expression compared to their unmodified counterparts in vivo. Notably, the one-component PAPs enable spleen-specific mRNA delivery, with their vaccine application validated in a mouse melanoma model following intravenous administration. Better still, PAPs can synergize with different helper lipids to formulate four-component lipid nanoparticles (LNPs), achieving respective lung- and liver-specific mRNA delivery. Noteworthy is that these organ-selective mRNA delivery systems significantly outperform previous polymer and LNP benchmarks. This transformation strategy for cationic polymers represents a generalized methodology to give highly effective mRNA carriers, highlighting substantial potential for clinical translation of mRNA therapies with organ-targeting requirements.

Dissecting the Spatial and Single-Cell Transcriptomic Architecture of Cancer Stem Cell Niche Driving Tumor Progression in Gastric Cancer.

Despite significant advancements in identifying novel therapeutic targets and compounds, cancer stem cells (CSCs) remain pivotal in driving therapeutic resistance and tumor progression in gastric cancer (GC). High-resolution knowledge of the transcriptional programs underlying the role of CSC niche in driving tumor stemness and progression is still lacking. Herein, spatial and single-cell RNA sequencing of 32 human gastric mucosa tissues at various stages of malignancy, illuminating the phenotypic plasticity of tumor epithelium and transcriptional trajectory from mature gastric chief cells to the CSC state, which is associated with activation of EGFR and WNT signaling pathways, is conducted. Moreover, the CSCs interact with not only the immunosuppressive CXCL13+ T cells and CCL18+ M2 macrophages to evade immune surveillance, but also the inflammatory cancer-associated fibroblasts (iCAFs) to promote tumorigenesis and maintain stemness, which construct the CSC niche leading to inferior prognosis. Notably, it is uncovered that amphiregulin (AREG) derived from iCAFs promotes tumor stemness by upregulating the expression of SOX9 in tumor cells, and contributes to drug resistance via the AREG-ERBB2 axis. This study provides valuable insight into the characteristics of CSC niche in driving tumor stemness and progression, offering novel perspective for designing effective strategies to overcome GC therapy resistance.

Psychological assessment and support in functional neurological disorder: a longitudinal study.

In the Department of Neuroscience in Clinical Neurological unit of our hospital, between 2020 and 2024, 58 adult patients were diagnosed with functional neurological disorder (FND). Out of these, 42 patients agreed to participate in a structured intervention consisting of 10 sessions of psychotherapy. This study aimed to investigate the demographic and clinical characteristics of the patient cohort, examine their reported symptoms, and evaluate the effectiveness and adherence to the psychotherapy program. The Affective Neuroscience Personality Scales (ANPS) were administered to assess the affective states of the patients, while the Shedler-Westen Assessment Procedure (SWAP-200) was used to evaluate their main personality style. A central objective of the research was to explore patterns or correlations between self-reported data from the patients and the evaluations completed by their therapists. This comparison sought to identify any alignment or discrepancies in the perception of symptoms and therapeutic progress, as measured by both the ANPS and SWAP-200 scales. The study's preliminary findings are reported to provide valuable insights into the impact of psychotherapeutic interventions for FND, including an understanding of the degree to which patient self-reports correspond with clinical assessments. These results will inform the optimization of treatment strategies and enhance patient outcomes by integrating patient feedback with clinical evaluations. The research contributes to the broader knowledge of FND management, emphasizing the importance of aligning patient and therapist perspectives in the therapeutic process.

Safety assessment of selinexor: a real-world pharmacovigilance study

ABSTRACT Background Selinexor is approved for the treatment of relapsed or refractory multiple myeloma. However, a comprehensive understanding of adverse events associated with selinexor is lacking. Methods Clinical trials of selinexor in patients with multiple myeloma were reviewed. We investigated selinexor-related adverse events through data of the US Food and Drug Administration Adverse Event Reporting System (FAERS). The disproportionality analysis was conducted. Four algorithms were employed to evaluate the signals of adverse events. The adverse effects of selinexor combined with dexamethasone were compared with bortezomib and dexamethasone. Sensitivity analysis was performed to exclude consumer-reported adverse events. The onset of adverse reactions were calculated. Results A total of 1,698 reports related with selinexor from FAERS were identified. 6 significant system organ class and 42 significant preferred terms (PTs) were found. Unexpected significant adverse events including mania, acute kidney injury, orthostatic hypotension, and embolisms were identified. 14 PTs reported significant signals in treatment of selinexor combined dexamethasone compared with traditional treatment of bortezomib and dexamethasone. 45.2% of adverse events occurred within the first month of starting selinexor. Conclusions Comprehensive analyses of selinexor related adverse events are helpful for clinical detection of adverse events and timely intervention, advancing selinexor’s therapeutic progress in future treatment.

Molecular Mechanisms and Therapeutic Targets of Hepatitis B Virus Pre-S Mutant-Associated Hepatocellular Carcinoma Tumorigenesis.

Background: Despite significant progress in diagnosis and therapeutics, hepatocellular carcinoma (HCC) is still among the most commonly occurring and life-taking human cancers globally, raising an urgent need for discovering effective therapeutic targets.Purpose: Chronic hepatitis B virus (HBV) infection is a major etiological factor associated with HCC development, progression, and prognosis. Pre-S mutants are naturally occurring mutated forms of HBV large surface proteins and predict a higher risk of HCC development and recurrence. Moreover, pre-S mutants function as important HBV oncoproteins which can promote HCC tumorigenesis through initiating a variety of oncogenic signaling pathways. Targeting pre-S mutant-induced oncogenic signaling pathways displays therapeutic potential in HCC.Research Design: This review summarizes the underlying molecular mechanisms of pre-S mutant-associated HCC tumorigenesis and highlights their potential in serving as therapeutic targets for HCC.

Nanoparticles in CNS Therapeutics: Pioneering Drug Delivery Advancements.

The incidence of Central Nervous System (CNS) disorders, including Parkinson's disease, Alzheimer's disease, stroke, and malignancies, has risen significantly in recent decades, contributing to millions of deaths annually. Efficacious treatment of these disorders requires medicines targeting the brain. The Blood-brain Barrier (BBB) poses a formidable challenge to effective drug delivery to the brain, hindering progress in CNS therapeutics. This review explores the latest developments in nanoparticulate carriers, highlighting their potential to overcome BBB limitations. This study aimed to evaluate and summarise the critical factors and pathways in the nanoparticle- based CNS targeted drug delivery. An extensive literature search was conducted, comprising the initial development of nanoparticle- based CNS-targeted drug delivery approaches to the latest advancements using various online search tools. The properties of nanoparticles, such as type of nanoparticles, size, shape, surface charge, hydrophobicity, and surface functionalisation, along with properties of the BBB during normal and pathological conditions and their impact on the delivery of nanoparticles across the BBB, are identified and discussed here. Important properties and pathways that determine the penetration of nanoparticles across the CNS are reviewed in this article, along with recent advances in the field.

Synergistic therapy with celastrol-curcumin multifunctional nanomedicine: Anti-hepatocellular carcinoma and reduced hepatotoxicity.

Synergistic therapy with celastrol-curcumin multifunctional nanomedicine: Anti-hepatocellular carcinoma and reduced hepatotoxicity.

Opportunities in the translational pipeline for pediatric brain cancer therapies.

Primary malignant central nervous system (CNS) tumors are the leading cause of cancer-related mortality in the pediatric population. Moreover, survivors often experience significant long-term treatment-related morbidity. Challenges unique to drug delivery to the central nervous system have hampered therapeutic progress. In the past decade, significant advancements in our understanding of molecular biology, genetic alterations, and the tumor microenvironment have allowed us to improve our in vitro and laboratory animal models to better replicate diseases seen in the pediatric population. Recently, a comparative approach using naturally-occurring CNS malignancies in dogs with similar disease progression, histologic presentation, and treatment response has been proposed as an enticing model system. Given these improvements in the translational pipeline, there is an opportunity to identify and implement effective therapies more efficiently to pediatric CNS malignancy populations. IMPACT: Relevant and translational pre-clinical studies are needed to find chemotherapeutics and targeted agents that can reach therapeutic doses within tumors in children without causing systemic adverse effects. A discussion of comparative oncology is provided with the intent to foster veterinary/human oncology collaboration. While the traditional pipeline for translating medications from bench to bedside has been evolving and improving over the last decade, the advances and remaining roadblocks of this pipeline are reviewed and discussed in this article.

Artificial intelligence for diagnosis and predictive biomarkers in Non-Small cell lung cancer Patients: New promises but also new hurdles for the pathologist.

Artificial intelligence for diagnosis and predictive biomarkers in Non-Small cell lung cancer Patients: New promises but also new hurdles for the pathologist.

Spatial transcriptomics and lethality-associated stromal remodeling of colorectal cancer.

227 Background: Colorectal cancer (CRC) is surgically resectable and eminently screenable yet remains a lethal entity with high affinity to metastasise synchronously and metachronously. It has been proposed that cellular and extracellular components of the microenvironment contribute to metastatic potential. Dissociative profiling techniques such as bulk transcriptomic and single-cell RNA sequencing have contributed insight but limited therapeutic progress. Spatial transcriptomic (ST) assessment allows molecular profiling of tissue while preserving tissue architecture. Here we employ ST approaches to interrogate tumor compartments of primary resectable and matched synchronous CRC demonstrating stromal signatures with distinct collagen expression associated with outcome. Methods: 25 patients with primary resectable CRC and 4 patients with matched primary CRC and liver metastasis (CRLM) underwent single-cell spatial transcriptomics using the Nanostring CosMx Spatial Molecular Imager (SMI, 1000plex gene panel) (Discovery cohort). 71681 epithelial and 88806 stromal cells with intact spatial resolution were analysed. The spatial single-cell signatures were reconstituted in 89 patients using the Nanostring GeoMx Digital Spatial Profiler (Validation cohort). 3 GeoMx compartments were analysed: Epithelial (PanCK+); Stroma (aSMA+); Immune (PanCK-aSMA-). Results: CosMx demonstrated 2 distinct collagen signatures: COL1A1,COL1A2,COL3A1 associated with normal fibroblasts; COL9A2 associated with cancer-related stroma and lethal subtypes of epithelial cell. In the GeoMx validation cohort, 42 patients expressed the COL1A1 signature in the aSMA compartment and 47 did not (5 year recurrence free survival: 0.88 vs 0.49, p < 0.005) with different morphological patterns of each distinct aSMA group. In patients with favourable prognosis, chemokine high epithelial subtypes expressed CXCL5 and recruited COL9A2-, IL6+ neutrophils to the surrounding microenvironment. In contrast, epithelial cells in patients with poor prognosis expressed CXCL8 and recruited COL9A2+ neutrophils which were frequently in contact with SPP1+ macrophages. Conclusions: We have used ST approaches to interrogate cellular compartments of CRC demonstrating stromal subtypes that impact outcome. These insights could be used in the clinical setting to quantify COL9A2 expression in aSMA+ cells to prognosticate patients. Targeting of tumor collagen has been proposed to augment existing anti-cancer therapies and this work has demonstrated COL9A2 as a potential target in need of further investigation.