Leiomyosarcoma Research Articles

Targeting the Molecular and Immunologic Features of Leiomyosarcoma.

Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.

A Rare Case of Synchronous Uterine Leiomyosarcoma and Endometrial Endometrioid Adenocarcinoma

Assessment Synchronous primary neoplasms are defined when two or more neoplasms take place concurrently in the same patient. Concomitant endometrial adenocarcinoma and uterine leiomyosarcoma are extremely rare. Here we present an extremely rare case of uterine leiomyosarcoma coexisting with endometrial endometrioid adenocarcinoma of the uterus. A 52 years old woman was reported to a gynecology outpatient clinic with chief complaints lower abdominal pain, severe dysmenorrhea, and irregular vaginal bleeding for 7 months. Ultrasound of pelvis and abdomen showed a solitary intramural fibroid measuring 10x10cm. Surgery was planned and a simple total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed and specimen was sent to the laboratory for examination. Histopathological examination from intramural mass showed high-grade leiomyosarcoma, spindle cell type with less than 50% of myometrial invasion. Sections from thickened endometrium showed endometrial endometrioid adenocarcinoma, FIGO grade I with an invasion of superficial fascicles of myometrium (<50%). Morphological diagnosis was supported by Immunohistochemistry. Here we report an exceptionally rare case of synchronous uterine leiomyosarcoma and endometrial endometrioid adenocarcinoma. Our study may contribute to understand the prognosis of such multiple malignancies, common associations, and etiology of the disease so that a proper plan for further management of the patient can be implemented.

Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor

IntroductionUterine leiomyosarcomas (uLMS) are rare, highly aggressive tumors. Up to 30% of uLMS may harbor gain of function (GOF) in the MAP2K4 gene, important for tumor cell proliferation, differentiation and metastasis. We investigated the in vivo activity of a novel MAP2K4 inhibitor, PLX8725, against uLMS harboring MAP2K4 gene-amplification. MethodsTwo fully characterized uLMS (i.e., LEY-11 and LEY-16) were grafted into female CB-17/SCID mice. Treatments with control vehicle or PLX8725 (50 mg/kg) were given via oral gavage daily on weekdays for up to 60 days. Tumor volume differences were calculated with two-way ANOVA. Pharmacokinetic (PK) and mechanistic studies of PLX8725 in uLMS PDX models were also performed. ResultsBoth uLMS tumors evaluated demonstrated GOF in MAP2K4 (i.e., 3 CNV in both LEY-11 and LEY-16). Tumor growth inhibition was significantly greater in both PDX LEY-11 and PDX LEY-16 treated with PLX8725 when compared to controls (p < 0.001). Median overall survival was also significantly longer in both PDX LEY-11 (p = 0.0047) and PDX LEY-16 (p = 0.0058) treatment cohorts when compared to controls. PLX8725 oral treatment was well tolerated, and PK studies demonstrated that oral PLX8725 gives extended exposure in mice. Ex vivo tumor samples after PLX8725 exposure decreased phosphorylated-ATR, JNK and p38, and increased expression of apoptotic molecules on western blot. ConclusionPLX8725 demonstrates promising in vivo activity against PDX models of uLMS harboring GOF alterations in the MAP2K4 gene with tolerable toxicity. Phase I trials of PLX8725 in advanced, recurrent, chemotherapy-resistant uLMS patients are warranted.

Sarcomas in fluid cytology: Experience from a tertiary care centre in India

Cytological evaluation of fluids for sarcomatous exfoliation is extremely rare. However, recently studies have come up describing characteristics of sarcomatous malignancies exfoliating into fluids but study from an Indian experience is still lacking. Description of clinico-pathological landscape in known cases of sarcomas, involving body fluid with emphasis on cytomorphologic details. Study includes cases reported as positive for involvement by sarcoma on fluid cytology including pleural, ascitic and cerebrospinal fluid (CSF) specimens between Jan 2016 to June 2022. Cases were retrieved and reviewed for cytomorphologic features which were subsequently correlated with its parent histology and IHC. IHC was applied on cell blocks for two cases where involvement was doubtful. In total, 21 fluid samples/cases including 4 CSF, 6 ascitic and 11 pleural fluid specimens were incorporated. Case spectrum comprised of 6 cases of Ewing Sarcoma (ES), 3 cases of rhabdomyosarcoma (RMS), 3 cases of osteosarcoma (OS), 2 cases of malignant peripheral nerve sheath tumor (MPNST), 2 cases of synovial sarcoma (SS), a case each of chondrosarcoma (CS), leiomyosarcoma (LMS) angiosarcoma (AS) and two cases of other malignancies with exfoliation of their sarcomatous component. Two cases presented as isolated latent metastasis so an IHC panel was applied to exclude involvement by secondary malignancy and prove involvement by primary diagnosed sarcoma.Majority of exfoliated sarcomas presented with epithelioidto pleomorphic morphology where at times it becomes obligatory to rule out occurrence of a secondary malignancy. It’s the first study from an Indian institute’s perspective that reflects upon such diversity of sarcomas with variability in morphology on exfoliation which can be overwhelming for a cytopathologist at times. IHC panel might be used when clinical background is unknown or when involvement is uncertain. More studies are needed that can help come up with recommendations that address such problems.

Primary leiomyosarcoma of tongue: A relatively uncommon entity occurring at an exceedingly rare site

Primary leiomyosarcoma (LMS) of the tongue is an extremely rare, highly aggressive malignancy associated with poor survival outcome. We report a case of 60 years old male who presented with growth left lateral border of tongue since 6 months. Histopathological examination of the excised growth confirmed the diagnosis of LMS. An exhaustive panel of immunohistochemical markers helped in ruling out other malignant spindle cell differentials.

Immunohistochemical markers in differential diagnosis of endometrial stromal sarcoma and leiomyosarcoma in an endometrial polyp: A case report

Leiomyosarcoma is the malignant counterpart of leiomyoma. It arises from smooth muscle of the uterus and is rare tumor that account for 2-5% of all uterine malignancy. We report a case of 60 years old female who presented with post menopausal bleeding with endometrial polyp. A total abdominal hysterectomy specimen was received in our center. A differential diagnosis of leiomyosarcoma/ Endometrial stromal sarcoma was made by histopathological examination. Immunohistochemistry report confirmed the diagnosis of uterine Leiomyosarcoma.

Downregulation of miR‑10b‑5p facilitates the proliferation of uterine leiomyosarcoma cells: A microRNA sequencing‑based approach.

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In addition, the molecular background of ULMS has not been fully elucidated due to its low incidence. Therefore, no effective treatment strategies have been established based on its molecular background. The present study aimed to investigate the roles of microRNAs (miRNAs/miRs) in the development of ULMS. Comprehensive miRNA sequencing was performed using six ULMS and three myoma samples, and revealed 53 and 11 significantly upregulated and downregulated miRNAs, respectively. One of the most abundant miRNAs in myoma samples was miR‑10b‑5p. The mean normalized read count of miR‑10b‑5p was 93,650 reads in myoma, but only 27,903 reads in ULMS. Subsequently, to investigate the roles of miR‑10b‑5p, gain‑of‑function analysis was performed using SK‑UT‑1 and SK‑LMS‑1 cell lines. The overexpression of miR‑10b‑5p suppressed cell proliferation and reduced the number of colonies. Moreover, miR‑10b‑5p increased the number of cells in the G1 phase. In conclusion, tumor‑suppressive miR‑10b‑5p was significantly downregulated in ULMS compared with in myoma; thus, miR‑10b‑5p may serve a specific role in sarcoma progression.

17P Exploiting the immune-modulatory effects of PI3K/mTOR inhibitors to enhance response to immune-checkpoint blockade in uterine leiomyosarcoma

17P Exploiting the immune-modulatory effects of PI3K/mTOR inhibitors to enhance response to immune-checkpoint blockade in uterine leiomyosarcoma

Late Recurrences in Soft Tissue Sarcomas - A Review

Sarcomas are malignant tumors that arise from the connective tissue. Soft tissue is part of connective tissue and includes fat, muscle, nerves, tendons, and blood and lymph vessels. Soft tissue sarcomas (STS) account for 1 percent of all adult cancers in the U.S. Leiomyosarcoma (LMS) is a type of STS that grows in smooth muscles. LMS accounts for 7-11% of all cases of STS. Generally, STS are treated with wide margin surgical resection and some patients are offered radiation and/or chemotherapy to decrease recurrence. Recurrences generally happen in the first two years and late recurrence is defined as appearance of original cancer after 5 years following initial treatment and being disease free. Late recurrences can be in the local area of the initial site or at a distant location. A patient with LMS in the left upper arm was treated with a curative intent with radiation and surgery in Kentucky in 2016. He relocated to Fort Worth, TX recently and was found to have the same LMS in the stomach in 2022, more than 5 years after his initial curative treatment. This prompted us to do literature review of late recurrences in STS. We found that late recurrences happen in 6-15% of patients with STS even if they survived 5 years without cancer following original cancer treatment. LMS accounts for 12% of all late recurrences. Only 27-36% of all STS patients are expected to be alive at 5 years from diagnosis of late distant recurrences.

Prognostic factors and outcomes of adult spermatic cord sarcoma. A study from the French Sarcoma Group

PurposeTo evaluate the outcomes of adult patients with spermatic cord sarcoma (SCS). MethodsAll consecutive patients with SCS managed by the French Sarcoma Group from 1980 to 2017 were analysed retrospectively. Multivariate analysis (MVA) was used to identify independent correlates of overall survival (OS), metastasis-free survival (MFS), and local relapse-free survival (LRFS). ResultsA total of 224 patients were recorded. The median age was 65.1 years. Forty-one (20.1%) SCSs were discovered unexpectedly during inguinal hernia surgery. The most common subtypes were liposarcoma (LPS) (73%) and leiomyosarcoma (LMS) (12.5%). The initial treatment was surgery for 218 (97.3%) patients. Forty-two patients (18.8%) received radiotherapy, 17 patients (7.6%) received chemotherapy. The median follow-up was 5.1 years. The median OS was 13.9 years. In MVA, OS decreased significantly with histology (HR, well-differentiated LPS versus others = 0.096; p = 0.0224), high grade (HR, 3 versus 1–2 = 2.7; p = 0.0111), previous cancer and metastasis at diagnosis (HR = 6.8; p = 0.0006). The five-year MFS was 85.9% [95% CI: 79.3–90.6]. In MVA, significant factors associated with MFS were LMS subtype (HR = 4.517; p < 10-4) and grade 3 (HR = 3.664; p < 10-3). The five-year LRFS survival rate was 67.9% [95% CI: 59.6–74.9]. In MVA, significant factors associated with local relapse were margins and wide reresection (WRR) after incomplete resection. OS was not significantly different between patients with initial R0/R1 resection and R2 patients who underwent WRR. ConclusionsUnplanned surgery affected 20.1% of SCSs. A nonreducible painless inguinal lump should suggest a sarcoma. WRR with R0 resection achieved similar OS to patients with correct surgery upfront.

Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.

Dedifferentiated leiomyosarcoma of the uterus: a clinicopathologic and immunohistochemical analysis of 23cases.

To morphologically and immunophenotypically characterize dedifferentiated uterine leiomyosarcoma (LMS). We identified 23 dedifferentiated uterine LMS, defined as a malignant uterine smooth muscle tumour containing discrete differentiated and dedifferentiated components (i.e. with and without morphologic and immunophenotypic evidence of smooth muscle differentiation, respectively). The differentiated component was leiomyosarcoma in most cases (17/23), though some arose from a leiomyoma (n=4) or smooth muscle tumour of uncertain malignant potential (n=2). The dedifferentiated tumour component showed noncohesive polygonal cells with moderate to abundant cytoplasm, pleomorphic nuclei with coarse vesicular to smudged chromatin, one or more macronucleoli, frequent multinucleation,and atypicalmitoses. Three cases showed heterologous osteosarcomatous or chondrosarcomatous differentiation. Immunohistochemistry revealed alterations characteristic of uterine LMS, including Rb loss (18/19); strong diffuse p16 (17/19); strong diffuse (9/19) or complete absence of (5/19) p53; and ATRX loss (6/16). Compared to a control cohort of uterine LMS without dedifferentiation, dedifferentiated uterine LMS showed significantly shorter disease-specific (median, 54 versus 20months; 5-year DSS, 46% versus 36%; P=0.04) and disease-free (median, 31 versus 8 months; 5-year DFS, 42% versus 8%; P=0.002) survival. Of 19 dedifferentiated uterine LMS with follow-up, 12 had died of disease at median 14 (range, 2-73)months; four were alive with disease at 4, 12, 44, and 50months; and three were alive with no evidence of disease at 56, 109, and 114months. Routine prospective recognition of dedifferentiated uterine LMS and distinction from mimics is advocated for accurate prognostication and for further characterisation of these tumours.

UTERINE LEIOMYOSARCOMA - A CASE REPORT

Leiomyomas are the most common mesenchymal neoplasms. Smooth muscle cells with variable amounts of fibrous stroma make up these benign tumors. The tumor occurs most frequently in uterus in 20–30% of women of reproductive age. Uterine leiomyosarcoma (uLMS/LMS) is a rare cancer originating from smooth muscle lining the walls of the uterus. We report a case of postmenopausal women of 65 years presented with retention urine, diagnosed as LMS of uterus on histopathology.

Association of chondroadherin with leiomyosarcoma

The leiomyosarcoma (LMS) subtype of uterine sarcoma accounts for 1–2 % of uterine neoplasia cases. The present study aimed to demonstrate that the gene and protein chondroadherin (CHAD) levels may serve as novel biomarkers for predicting prognosis and devising novel treatment models for LMS. A total of 12 patients diagnosed with LMS and 13 patients diagnosed with myomas were included in the study. The extent of tumour cell necrosis, cellularity and atypia and the mitotic index of each patient with LMS were determined. CHAD gene expression was significantly increased in cancerous tissues compared with that in fibroid tissues (2.17 ± 0.88 vs 3.19 ± 1.61; P = 0.047). The mean CHAD protein expression in tissues was higher in LMS cases but this was not statistically significant (217.38 ± 93.9 vs 177.13 ± 66.67;P = 0.226). Positive significant correlations were obtained between CHAD gene expression and mitotic index (r = 0.476; P = 0.008), tumour size (r = 0.385; P = 0.029) and necrosis (r = 0.455; P = 0.011). Furthermore, there were significant positive correlations between CHAD protein expression levels and tumour size (r = 0.360; P = 0.039) and necrosis (r = 0.377; P = 0.032). The present study was the first to demonstrate the significance of CHAD in LMS. The results suggested that, due to its association with LMS, CHAD has predictive value in determining the prognosis of patients with LMS.

Overlap of Suspicious and Non-Suspicious Features in the Ultrasound Evaluations of Leiomyosarcoma: A Single-Center Experience.

Leiomyosarcoma (LMS) is a rare type of mesenchymal tumor. Suspecting LMS before surgery is crucial for proper patient management. Ultrasound is the primary method for assessing myometrial lesions. The overlapping of clinical, laboratory, as well as ultrasound features between fibroids and LMS makes differential diagnosis difficult. We report our single-center experience in ultrasound imaging assessment of LMS patients, highlighting that misleading findings such as shadowing and absent or minimal vascularization may also occur in LMS. To avoid mistakes, a comprehensive evaluation of potentially overlapping ultrasound features is necessary in preoperative ultrasound evaluations of all myometrial tumors.

Neutrophil-to-Lymphocyte Ratio (NLR) for Preoperative Differentiation between Uterine Leiomyosarcoma (LMS) and Uterine Leiomyoma: A Case-Controlled Study

Differentiating uterine LMS from uterine leiomyoma is difficult. Therefore, this study aimed to compare preoperative NLR of uterine leiomyosarcoma (LMS) with leiomyoma and secondary objective aimed to identify the clinical characteristics to distinguish between uterine LMS and uterine leiomyoma including the appropriate NLR cut off value to differentiate LMS from leiomyoma. This was a matched case-controlled study with 1:4 ratio. We collected data of patients with uterine LMS and leiomyoma from 2011 to 2020 at King Chulalongkorn Memorial Hospital. Patients with uterine LMS (case group) and leiomyoma (control group) were matched in terms of year of the surgery and size of the uterine mass. Statistical analysis was conducted using SPSS version 22.0 and STATA version 17. Conditional logistic regression analysis with a p-value of <0.05 was used. Twenty-seven patients who were diagnosed with uterine LMS met the inclusion criteria; 13 patients who had incomplete data and one patient who was had concurrent breast cancer were excluded. Thirteen patients were included in the final analysis. From 2,587 patients in control group; 52 patients were matched. The baseline characteristics in both groups were comparable except for menopausal status Women with uterine LMS had a higher NLR than those with leiomyoma (mean, 4.56 ± 2.5 and 2.4 ± 1.15 in the case and control groups, respectively). Conditional logistic regression determined that the NLR cut-off value of 2.8 was a statistically significant factor for determining uterine LMS (OR = 3.24; 95% CI 1.01-10.43). No significant difference was found in the other factors. Patients who were diagnosed with uterine LMS had a significantly higher NLR than those diagnosed with leiomyoma. The NLR is a simple and effective method for predicting the presence of a uterine LMS in patients who are pre-operatively diagnosed with a uterine mass.

MiR-130b modulates the invasive, migratory, and metastatic behavior of leiomyosarcoma.

Leiomyosarcoma (LMS) is an aggressive, often poorly differentiated cancer of the smooth muscle (SM) lineage for which the molecular drivers of transformation and progression are poorly understood. In microRNA (miRNA) profiling studies, miR-130b was previously found to be upregulated in LMS vs. normal SM, and down-regulated during the differentiation of mesenchymal stem cells (MSCs) into SM, suggesting a role in LMS tumor progression. In the present study, the effects of miR-130b on human LMS tumorigenesis were investigated. Stable miR-130b overexpression enhanced invasion of LMS cells in vitro, and led to the formation of undifferentiated, pleomorphic tumors in vivo, with increased growth and metastatic potential compared to control LMS cells. TSC1 was identified as a direct miR-130b target in luciferase-3'UTR assays, and shRNA-mediated knockdown of TSC1 replicated miR-130b effects. Loss-of-function and gain-of-function studies showed that miR-130b levels regulate cell morphology and motility. Following miR-130b suppression, LMS cells adopted a rounded morphology, amoeboid mode of cell movement and enhanced invasive capacity that was Rho/ROCK dependent. Conversely, miR-130b-overexpressing LMS cells exhibited Rho-independent invasion, accompanied by down-regulation of Rho-pathway effectors. In mesenchymal stem cells, both miR-130b overexpression and TSC1 silencing independently impaired SM differentiation in vitro. Together, the data reveal miR-130b as a pro-oncogenic miRNA in LMS and support a miR-130b-TSC1 regulatory network that enhances tumor progression via inhibition of SM differentiation.

High-Grade Sarcomas with Myogenic Differentiation Harboring Hotspot PDGFRB Mutations

PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented in sarcomas with myogenic differentiation. Driven by occasional sarcomas harboring PDGFRB mutations, we investigated their prevalence and clinicopathologic and genomic features in a large cohort of sarcomas. An institutional targeted DNA next-generation sequencing database was searched for sarcomas with myogenic differentiation harboring hotspot PDGFRB gene alterations. Among 3300 patients with sarcomas, 21 (0.6%) patients were identified (17 women, 4 men) with an age range of 35 to 88 years. The site distribution included 13 gynecologic tract (12 uteri, 1 vagina), 4 bone and soft tissue, and 4 viscera. All except 1 were high grade. Most patients were diagnosed as sarcomas with myogenic differentiation based on partial staining for 1 or more muscle markers, whereas 6 were labeled as leiomyosarcoma (LMS). Most tumors showed monomorphic spindle morphology, with either heterogeneous features of myofibroblastic and smooth muscle differentiation or an undifferentiated phenotype. Hormone receptors were negative in all uterine cases. PDGFRB immunostaining in all cases tested was strong and diffuse, whereas PDGFRA was negative/focal. The most frequent PDGFRB mutations were exon 12 (43%), exon 14 (N666K/S/T) (38%), and exon 18 (D850Y/H/V or insertion/deletion) (19%). The most frequent co-existing genetic alterations (26% to 37%) occurred in CDKN2A/B, TP53, TERT, and MED12. Moreover, PDGFRB-mutant sarcomas had an overall distinct genomic landscape compared with both uterine and soft tissue LMS control groups. These tumors were associated with a highly aggressive clinical course, with frequent distant metastases (81%) and death (76%), regardless of anatomic location, and worse overall survival compared with the 2 LMS control groups. This is the first study documenting recurrent hotspot PDGFRB alterations in high-grade sarcomas, which show a predilection for uterine location and myogenic differentiation that fall short of the diagnostic criteria for LMS. Further studies are needed to investigate the therapeutic potential of kinase inhibitors in this group of tumors.

Uterine Leiomyosarcoma: A Rare Entity

Uterine leiomyosarcoma is a rare uterine malignancy that arises from the smooth muscle of uterine wall. Presenting symptoms may be vague and mimic other benign uterine conditions. They are notoriously aggressive with poor prognosis. We report a case of a 35-year-old female, who presented with abdominal distension with pain and vomiting. A non-tender mass measuring 14X12 cms was felt on palpation in the same region. CT scan revealed a large, relatively well defined, hypodense pelvic mass in retro-uterine pouch. Patient underwent exploratory laparotomy with primary resection of tumour with pan-hysterectomy with pelvic lymph node resection. Histopathologically, it was diagnosed as pleomorphic sarcoma probably leiomyosarcoma of uterus which showed immunostain Smooth Muscle Antigen (SMA) positive and Epithelial Membrane Antigen (EMA) negative. It was Estrogen Receptor(ER) negative. The rarity as well as pathological diversity makes this study beneficial and this definitive reporting will be helpful in diagnosis of smooth muscle tumours with challenging histologic features.

Distinct Cellular Origins and Differentiation Process Account for Distinct Oncogenic and Clinical Behaviors of Leiomyosarcomas.

In leiomyosarcoma (LMS), a very aggressive disease, a relatively transcriptionally uniform subgroup of well-differentiated tumors has been described and is associated with poor survival. The question raised how differentiation and tumor progression, two apparently antagonist processes, coexist and allow tumor malignancy. We first identified the most transcriptionally homogeneous LMS subgroup in three independent cohorts, which we named 'hLMS'. The integration of multi-omics data and functional analysis suggests that hLMS originate from vascular smooth muscle cells and show that hLMS transcriptional program reflects both modulations of smooth muscle contraction activity controlled by MYOCD/SRF regulatory network and activation of the cell cycle activity controlled by E2F/RB1 pathway. We propose that the phenotypic plasticity of vascular smooth muscle cells coupled with MYOCD/SRF pathway amplification, essential for hLMS survival, concomitant with PTEN absence and RB1 alteration, could explain how hLMS balance this uncommon interplay between differentiation and aggressiveness.