Pham, T. T. Q. and Rita YH Huang
Taipei Medical University, Taipei
Human skin represents one of nature’s most sophisticated examples of tissue homeostasis, functioning as an intricate biological system that seamlessly balances protection, regeneration, and adaptive responses to environmental stressors. Normal skin homeostasis operates through a carefully orchestrated cellular hierarchy, where skin stem cells (SSCs) serve as the foundational architects of epidermal integrity. The outermost layer of our skin, the epidermis, functions not merely as a passive protective barrier but as a dynamic, mechanically responsive tissue that continuously renews itself through precisely regulated cellular processes.
SSCs, a population of long-lived basal stem cells, strategically positioned at the boundary between the epidermis and dermis. These cellular guardians possess the extraordinary capacity for unlimited self-renewal while simultaneously generating daughter cells destined for differentiation. The progeny of these stem cells, known as transient amplifying cells, embark on cellular maturation, progressively moving through distinct epidermal layers as they undergo terminal differentiation, ultimately forming the protective cornified envelope that shields us from environmental harm.
The delicate equilibrium maintained by this cellular ecosystem is fundamental to skin health and function. When this balance is disrupted, the consequences can be catastrophic, leading to hyperproliferative disorders, chronic inflammatory conditions, or the development of malignant neoplasms. Understanding the mechanisms that govern this balance has become increasingly critical as we witness a global surge in skin cancer incidence, making cutaneous malignancies one of the most pressing public health challenges of our time.
The Escalating Global Burden of Cutaneous Malignancies
The contemporary landscape of skin cancer epidemiology presents a sobering reality that demands urgent attention from the global medical community. Cutaneous malignancies, encompassing both melanoma and non-melanoma variants, have experienced unprecedented increases in incidence rates across diverse populations worldwide.
Melanoma, while representing a smaller fraction of total skin cancer cases, commands particular attention due to its exceptional lethality and aggressive biological behavior. This malignancy demonstrates an almost unparalleled capacity for metastatic dissemination, often occurring through complex mechanisms. According to GLOBOCAN 2022 data, melanoma ranks as the 22nd leading cause of cancer deaths worldwide1—underscoring its severe impact. The clinical reality of advanced melanoma presents formidable challenges for both patients and healthcare providers. Individuals diagnosed with stage IV disease face particularly grim prospects, with five-year survival rates hovering around 22.5%2, despite advances in therapeutic approaches. This poor prognosis reflects the inherent biological aggressiveness of advanced melanoma, characterized by its remarkable capacity for treatment resistance and genetic instability. Epidemiological modeling suggests that by 2040, global melanoma cases will increase by approximately 50%, with new diagnoses potentially reaching 510,000 annually3. Even more alarming is the projected 68% increase in mortality, with deaths potentially rising to 96,000 annually compared to 2020 baseline figures3.
Melanoma often steals the spotlight because of its deadly nature, but the quieter epidemic of non-melanoma skin cancers affects far more people each year. These mainly include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), both of which pose a significant challenge to healthcare systems worldwide. BCC accounts for about 70% of non-melanoma cases, while SCC makes up around 25%4. The epidemiological trends for non-melanoma skin cancers reveal a disturbing pattern of consistent increase over the past three decades. BCC incidence has surged by 20% to 80% annually, while SCC rates have increased by 3% to 10% per year5. The year 2022 witnessed 1,234,533 new non-melanoma skin cancer cases globally, resulting in 69,416 deaths according to comprehensive global cancer statistics6.
SCC, in particular, presents unique challenges due to its aggressive biological behavior and capacity for invasive growth. This malignancy contributed to approximately 56,000 deaths in 2019 according to global health surveys, highlighting its significant mortality impact7. When SCC progresses to invasive stages, the prognosis becomes particularly dire, with 10-year survival rates dropping below 20% for advanced cases8. The global burden of cutaneous SCC reached 2,402,221 cases in 2019, with death rates increasing by 6.1% between 1990 and 20199. Projections for 2035 estimate 3,637,626 cases, representing a staggering 51.4% increase from 2019 levels9.
Skin cancer stem cells: the architects of treatment resistance
The concept of skin cancer stem cells (CSCs) has revolutionized our understanding of malignant biology, particularly in the context of cutaneous malignancies. These specialized cellular populations possess characteristics that set them apart from bulk tumor cells, including enhanced self-renewal capacity, resistance to conventional therapeutic approaches, and the ability to generate heterogeneous tumor populations. In aggressive skin cancers, the persistent self-renewal and expansion of CSCs correlate directly with poor clinical outcomes, treatment resistance, and invasive behavior.
The identification and characterization of CSC populations in skin malignancies have revealed remarkable cellular diversity and complexity. In melanoma, researchers have identified multiple distinct CSC subpopulations, each characterized by specific molecular markers and functional properties. These include cells expressing CD133 (Cluster of Differentiation 133), a glycoprotein associated with stem cell properties and treatment resistance10. Additionally, ABCB5-positive cells, characterized by expression of ATP-binding cassette sub-family B member 5, demonstrate enhanced drug efflux capabilities that contribute to chemotherapy resistance11. The enzyme aldehyde dehydrogenase (ALDH) serves as another critical marker for melanoma CSCs, playing essential roles in cellular metabolism and detoxification processes that enhance survival under therapeutic stress12. CD20-positive melanoma cells represent yet another distinct subpopulation with stem cell characteristics13, while CD271-expressing cells demonstrate particular relevance to neural crest-derived melanoma biology14. The transcription factor SOX10 (SRY-Box transcription factor) marks additional CSC populations that maintain developmental programs associated with melanocyte lineage specification15.
Similarly, SCC and BCC harbor distinct cancer stem cell subpopulations that contribute to tumor initiation, progression, and therapeutic resistance. These cellular populations demonstrate remarkable plasticity, adapting to therapeutic pressures through various mechanisms including metabolic reprogramming, enhanced DNA repair capabilities, and activation of survival signaling pathways.
The microenvironmental niche: orchestrating cellular fate decisions
The fate determination of both normal SSCs and CSCs occurs within specialized microenvironmental niches that provide essential regulatory signals and structural support. These niches function as sophisticated cellular ecosystems where multiple cell types, signaling molecules, and structural components collaborate to maintain tissue homeostasis or, alternatively, promote malignant transformation and progression.
In normal SSC niches, several core signaling pathways maintain the delicate balance between self-renewal and differentiation. The Sonic Hedgehog (Shh) pathway plays fundamental roles in stem cell maintenance and tissue patterning, regulating cellular proliferation and differentiation decisions through complex transcriptional networks. The Wingless-related integration site (Wnt)/β-catenin signaling cascade serves as another critical regulatory mechanism, controlling stem cell fate decisions and tissue regeneration processes. The Notch signaling pathway contributes additional layers of regulation, mediating cell-cell communication and fate specification through direct intercellular interactions. Meanwhile, the YAP (Yes-associated protein)/TAZ (Transcriptional co-activator with PDZ-binding motif) pathway integrates mechanical and biochemical signals to regulate stem cell behavior and growth. These pathways work together with other parts of the stem cell niche—such as adhesion signals, the dermal-epidermal border, and the surrounding diverse cells—to keep stem cells in balance. It’s a fine-tuned act: providing just enough activity to preserve their regenerative potential while preventing uncontrolled growth. This quiet coordination draws the line between healthy tissue renewal and unchecked proliferation.
However, in CSC niches, this carefully orchestrated regulatory system becomes dysregulated, leading to aberrant cellular behavior and malignant transformation. In treatment-resistant skin cancers, CSC niches are shaped by a mix of disrupted signals and oncogenic pathways—especially PI3K/AKT/mTOR and JAK/STAT3. These signaling changes don’t just help CSCs survive; they actively support their growth and protect them from therapy. Even when treatments manage to target the bulk of the tumor, these niche-driven pathways can help a small group of stem-like cells escape, adapt, and eventually cause the cancer to return. This makes the niche itself a major obstacle, reinforcing resistance and making it harder to fully eliminate the disease. Therefore, understanding and targeting these pathways may be essential to improving outcomes.
Therapeutic implications and future directions
CSCs and their niche are no longer passive footnotes in tumor biology—they are the tacticians behind resistance, relapse, and relentless progression. In many advanced cases, patients face poor outcomes—not just because of the cancer’s spread, but because conventional therapies often can’t eliminate the small, resilient population of CSCs hiding within complex microenvironments. These cells are experts at survival, protected by signals from their niche. While this insight opens new possibilities for targeted treatments, developing therapies that can effectively disrupt these interactions without harming healthy tissue remains a major challenge.
Targeting CSC niches represents a promising therapeutic strategy, particularly for refractory skin cancers that have failed conventional treatment approaches. This approach recognizes that effective cancer treatment requires not only elimination of bulk tumor cells but also disruption of the specialized microenvironments that sustain CSC populations. Current clinical investigations are exploring various strategies to target niche signaling pathways, including inhibitors of Shh, Wnt, Notch, and YAP/TAZ signaling, as well as combination approaches that simultaneously target multiple pathways.
Key components of the stem cell niche, such as integrins and their ligand laminins, function with a dual identity. Under physiological conditions, they orchestrate orderly epidermal differentiation and tissue stability. However, when their expression patterns are altered, these same molecules shift roles—supporting the survival, self-renewal, and expansion of CSCs. This functional duality presents a therapeutic conundrum: targeting these adhesive signals may suppress tumorigenic potential, but risks disrupting essential regenerative processes in normal skin. Additionally, the dermo-epidermal junction, adherens junctions, and various cell types including immune cells and fibroblasts all contribute to niche function and represent potential therapeutic targets.
Conclusion: toward precision medicine in skin cancer treatment
In this review, we reframed the dynamic dialogue between SSCs and their surrounding microenvironments as a central narrative in both skin maintenance and cancer development16. Additionally, we summarized clinical trials targeting core signaling in skin CSC niches and highlight how comprehensive understanding of CSC niche biology can inform effective therapeutic strategies to overcome treatment resistance and improve patient outcomes16. Despite strides in decoding these cellular communication, many of the molecular cues that dictate how CSCs engage with their niches remain elusive. Notably, pockets of treatment resistance are often traced back to these resilient cell populations that escape conventional therapies. To move the field forward, future investigations should turn a sharper lens on the two-way communication between cutaneous CSCs and their niche habitats. Unraveling these interactions may hold the key to unlocking more durable therapeutic strategies for skin malignancies and overcoming drug resistance at its root. The development of precision medicine approaches that account for the heterogeneity of CSC populations and their niche dependencies will be essential for improving outcomes in patients with aggressive skin malignancies.
References
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