Cancer-Associated Fibroblasts and Their Role in Skin Cancer Progression
Cancer-associated fibroblasts (CAFs) have recently been recognized as pivotal contributors to cancer progression and treatment outcomes. This insight is particularly significant in skin cancers such as basal cell carcinoma, squamous cell carcinoma, and melanoma. Through an in-depth analysis using molecular and spatial single-cell techniques, researchers have identified three distinct CAF subtypes, each playing unique roles in the tumor microenvironment. This article explores the composition and influence of these fibroblast types on skin cancer progression.
Intra-tumoral Diversity of CAFs in Skin Cancer
Recent studies have dissected the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma. With advanced molecular and spatial single-cell analysis, three distinct CAF subtypes were identified: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-scale tissue analysis across various stages of cancer progression has revealed significant shifts in CAF subtype patterns, which appear to correlate with increasing malignancy.
Role of CAF Subtypes in Cancer Progression and Immune Interaction
In the complex landscape of cancer progression, these CAF subtypes play vital roles. For instance, mCAFs are known to synthesize extracellular matrix components, potentially restricting T cell invasion in lower-grade tumors by encapsulating tumor nests. On the other hand, iCAFs are predominantly present in late-stage tumors, producing high levels of cytokines and chemokines to aid immune cell recruitment and activation. These activities can alter the tumor microenvironment, influencing both tumor growth and immune surveillance.
The Tumor Microenvironment and Fibroblast Heterogeneity
The tumor microenvironment (TME) is a dynamic component of cancer progression, with fibroblasts acting as key cellular constituents. Traditionally viewed as structural cells aiding in tissue repair, fibroblasts are now understood to exhibit plasticity and functional heterogeneity, significantly impacting cancer progression and treatment. This functional diversity within fibroblasts is critical, as some subtypes can support tumor growth while others may slow it down.
Examining Fibroblast Heterogeneity in Skin Cancer
Previous studies mainly focused on tumor-infiltrating lymphocytes in skin cancers, often overlooking the role of fibroblasts. Recent research has highlighted the presence of multiple fibroblast subtypes within a single tumor, each with distinct functions. The advent of single-cell RNA sequencing (scRNA-seq) technologies has been instrumental in uncovering this heterogeneity. While fibroblast diversity has been studied in various cancers, such as breast and pancreatic cancers, a detailed analysis for skin cancer was lacking until now.
Mapping Fibroblast Diversity in Skin Cancer Using Advanced Techniques
Researchers employed the sensitive Smart-seq2 scRNA-seq technology alongside in situ mRNA staining to study fibroblast heterogeneity in basal cell carcinoma, squamous cell carcinoma, and melanoma. By analyzing both cancerous and adjacent non-lesional tissues, they aimed to map the similarities and differences in fibroblast subtypes across different stages and types of skin cancer.
CAF Subtypes and Their Distribution in Skin Cancer Tissues
An in-depth cell atlas creation from biopsy samples across various skin cancer types enabled researchers to delve into fibroblast subtype distribution. Utilizing flow cytometry and Smart-seq2 technology, they enriched samples for fibroblasts to observe how these cells segregate into different CAF clusters. This led to a better understanding of the distinct expression patterns and roles of fibroblast subtypes in cancer pathogenesis.
The Impact of Tumor Microenvironment on Non-malignant Cells
Investigations into the TME have shown how it influences non-malignant cell types, including fibroblasts and melanocytes. Through CNV analysis and clustering strategies, researchers could identify tumor-specific changes in gene expression, shedding light on how the microenvironment changes even normal cellular properties.
A Closer Look at Distinct Fibroblast Populations in Skin Cancer
The intricate landscape of fibroblast populations in skin cancer includes mCAFs, iCAFs, and RGS5+ fibroblasts, among others. Each subtype presents unique gene expression profiles, indicating distinct functions. For instance, mCAFs are associated with extracellular matrix production, crucial for forming barriers around tumors. In contrast, iCAFs express a variety of immunomodulatory molecules, highlighting their role in immune cell recruitment.
Probing the Functional Trajectories of Fibroblast Subtypes
Exploratory analyses using trajectory inference models reveal potential differentiation routes from healthy fibroblasts to CAFs. This insight suggests mCAFs may transform into iCAFs over time, highlighting a progressive adaptation to the tumorigenic environment.
CAF Subtypes as Potential Therapeutic Targets
Given the significant roles CAF subtypes play in cancer microenvironments, they present themselves as promising targets for enhancing the efficacy of immunotherapies in skin cancers. Understanding the mechanisms by which different CAF populations interact with tumor and immune cells could lead to innovative treatments that target specific fibroblast subtypes.
In Situ Validation and Spatial Distribution of Fibroblast Subtypes
By validating these subtypes through in situ mRNA analysis, researchers confirmed their spatial distribution within tumors, offering a clearer picture of how their presence correlates with cancer aggression and progression.
The Role of mCAFs in Tumor Defense and T Cell Exclusion
Analysis of the mCAFs has shown that their matrix production plays a defensive role, potentially forming barriers that limit immune cell ingress into tumor tissues. The presence and density of mCAFs were also found to correlate inversely with T cell infiltration, suggesting a mechanism of immune exclusion in tumors.
iCAFs as Key Drivers of Immune Activation and Recruitment
In contrast, iCAFs produce a suite of cytokines and chemokines, significantly influencing the immune landscape within tumors. Their expression of immunomodulatory factors positions them as key facilitators in immune cell recruitment and immune surveillance, making them crucial players in the interplay between cancer progression and immune response.
Conclusion on CAF Heterogeneity in Skin Cancer
Fibroblast diversity in skin cancers underscores the complex interactions within the tumor microenvironment, with distinct fibroblast subtypes contributing uniquely to cancer dynamics. Continued research will further elucidate these roles, potentially guiding novel therapeutic strategies that specifically modulate CAF functions to improve treatment outcomes in skin cancers.
출처 : Original Source