RESUMEN
Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialized inflammatory microenvironment.
Asunto(s)
Inflamación , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Animales , Inflamación/patología , Inflamación/metabolismo , Ratones , Línea Celular Tumoral , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Carcinoma Basocelular/patología , Carcinoma Basocelular/inmunología , Carcinoma Basocelular/metabolismo , Resistencia a Antineoplásicos , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Células del Estroma/patología , Células del Estroma/metabolismo , FN-kappa B/metabolismo , Análisis de la Célula Individual , Regulación Neoplásica de la Expresión GénicaRESUMEN
Skin fibrosis is characterized by fibroblast activation and intradermal fat loss, resulting in excess deposition and remodeling of dermal extracellular matrix (ECM). The topography of the dominant ECM proteins, such as collagens, can indicate skin stiffness and remains understudied in evaluating fibrotic skin. Here, we adapted two different unbiased image analysis algorithms to define collagen topography and alignment in a genetically inducible and reversible Wnt activation fibrosis model. We demonstrated that Wnt-activated fibrotic skin has altered collagen fiber characteristics and a loss of collagen alignment, which were restored in the reversible model. This study highlights how unbiased algorithms can be used to analyze ECM topography, providing novel avenues to evaluate fibrotic skin onset, recovery, and treatment.
RESUMEN
Although basal cell carcinomas arise from ectopic Hedgehog pathway activation and can be treated with pathway inhibitors, sporadic basal cell carcinomas display high resistance rates, whereas tumors arising in patients with Gorlin syndrome with germline Patched (PTCH1) alterations are uniformly suppressed by inhibitor therapy. In rare cases, patients with Gorlin syndrome on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. In this study, we report a case of an SMO inhibitor-resistant tumor arising in a patient with Gorlin syndrome on suppressive SMO inhibitor for nearly a decade. Using a combination of multiomics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO inhibitors through the previously described basal to squamous cell carcinoma transition. Intriguingly, through spatial whole-exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of basal to squamous cell carcinoma transition resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO inhibitors for not only Gorlin syndrome but also sporadic basal cell carcinomas.
Asunto(s)
Síndrome del Nevo Basocelular , Carcinoma Basocelular , Carcinoma de Células Escamosas , Resistencia a Antineoplásicos , Neoplasias Cutáneas , Receptor Smoothened , Humanos , Síndrome del Nevo Basocelular/genética , Síndrome del Nevo Basocelular/patología , Síndrome del Nevo Basocelular/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptor Smoothened/genética , Receptor Smoothened/antagonistas & inhibidores , Receptor Smoothened/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma Basocelular/genética , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Masculino , Anilidas/uso terapéutico , Femenino , Transducción de Señal/efectos de los fármacos , Piridinas/uso terapéuticoRESUMEN
While basal cell carcinomas (BCCs) arise from ectopic hedgehog pathway activation and can be treated with pathway inhibitors, sporadic BCCs display high resistance rates while tumors arising in Gorlin syndrome patients with germline Patched ( PTCH1 ) mutations are uniformly suppressed by inhibitor therapy. In rare cases, Gorlin syndrome patients on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. Here we report a case of an SMO i -resistant tumor arising in a Gorlin patient on suppressive SMO i for nearly a decade. Using a combination of multi-omics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO i through the previously described basal to squamous cell carcinoma transition (BST). Intriguingly, through spatial whole exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as novel genetic suppressors of BST resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO i for not only Gorlin syndrome but sporadic BCCs as well.
RESUMEN
Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the heterogeneous basal cell carcinoma tumor epithelia. Within the highly proliferative neighborhood, we find that TREM2+ skin cancer-associated macrophages (SCAMs) support the proliferation of a distinct tumor epithelial population through an immunosuppression-independent manner via oncostatin-M/JAK-STAT3 signaling. SCAMs represent a unique tumor-specific TREM2+ population defined by VCAM1 surface expression that is not found in normal homeostatic skin or during wound healing. Furthermore, SCAMs actively proliferate and self-propagate through multiple serial tumor passages, indicating long-term potential. The tumor rapidly drives SCAM differentiation, with intratumoral injections sufficient to instruct naive bone marrow-derived monocytes to polarize within days. This work provides mechanistic insights into direct tumor-immune niche dynamics independent of immunosuppression, providing the basis for potential combination tumor therapies.
Asunto(s)
Carcinoma Basocelular , Neoplasias Cutáneas , Humanos , Macrófagos/metabolismo , Monocitos , Carcinogénesis/metabolismo , Carcinoma Basocelular/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
Fibrosis is the life-threatening, excessive accumulation of the extracellular matrix and is sometimes associated with a loss of lipid-filled cells in the skin and other organs. Understanding the mechanisms of fibrosis and associated lipodystrophy and their reversal may reveal new targets for therapeutic intervention. In vivo genetic models are needed to identify key targets that induce recovery from established fibrosis. Wnt signaling is activated in animal and human fibrotic diseases across organs. Here, we developed a genetically inducible and reversible Wnt activation model and showed that it is sufficient to cause fibrotic dermal remodeling, including extracellular matrix expansion and shrinking of dermal adipocytes. Upon withdrawal from Wnt activation, Wnt-induced fibrotic remodeling was reversed in mouse skin-fully restoring skin architecture. Next, we demonstrated CD26/ DPP4 is a Wnt/ß-catenin-responsive gene and a functional mediator of fibrotic transformation. We provide genetic evidence that the Wnt/DPP4 axis is required to drive fibrotic dermal remodeling and is associated with human skin fibrosis severity. Remarkably, DPP4 inhibitors can be repurposed to accelerate recovery from established Wnt-induced fibrosis. Collectively, this study identifies Wnt/DPP4 axis as a key driver of extracellular matrix homeostasis and dermal fat loss, providing therapeutic avenues to manipulate the onset and reversal of tissue fibrosis.