Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-ß1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-ß1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-ß1 signaling axis.

Overcoming Nutrient Stress: Integrin αvß3-Driven Metabolic Adaptation Supports Tumor Initiation.

Nutrient stress accompanies several stages of tumor progression, including metastasis formation. Metabolic reprogramming is a hallmark of cancer, and it has been associated with stress tolerance and anchorage-independent cell survival. Adaptive responses are required to support cancer cell survival under these conditions. In this issue of Cancer Research, Nam and colleagues showed that the extracellular matrix (ECM) receptor integrin ß3 was upregulated in lung cancer cells in response to nutrient starvation, resulting in increased cell survival that was independent from ECM binding. Delving into the molecular mechanisms responsible for this, the authors found that integrin ß3 promoted glutamine metabolism and oxidative phosphorylation (OXPHOS) by activating a Src/AMPK/PGC1α signaling pathway. Importantly, in vivo experiments confirmed that OXPHOS inhibition suppressed tumor initiation in an orthotopic model of lung cancer, while ß3 knockout completely abrogated tumor initiation. These observations indicate that targeting signaling pathways downstream of αvß3 could represent a promising therapeutic avenue to prevent lung cancer progression and metastasis. See related article by Nam et al., p. 1630.

Extraneural metastatic ependymoma: distant metastasis to the pleura, lungs, lymph nodes and bone.

Ependymomas are neuroepithelial tumours arising from ependymal cells surrounding the cerebral ventricles that rarely metastasise to extraneural structures. This spread has been reported to occur to the lungs, lymph nodes, liver and bone. We describe the case of a patient with recurrent CNS WHO grade 3 ependymoma with extraneural metastatic disease. He was treated with multiple surgical resections, radiation therapy and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space and lymph nodes.

CLIP170 inhibits the metastasis and EMT of papillary thyroid cancer through the TGF-ß pathway.

Metastasis poses a significant challenge in combating tumors. Even in papillary thyroid cancer (PTC), which typically exhibits a favorable prognosis, high recurrence rates are attributed to metastasis. Cytoplasmic linker protein 170 (CLIP170) functions as a classical microtubule plus-end tracking protein (+TIP) and has shown close association with cell migration. Nevertheless, the specific impact of CLIP170 on PTC cells remains to be elucidated. Our analysis of the GEO and TCGA databases unveiled an association between CLIP170 and the progression of PTC. To explore the impact of CLIP170 on PTC cells, we conducted various assays. We evaluated its effects through CCK-8, wound healing assay, and transwell assay after knocking down CLIP170. Additionally, the influence of CLIP170 on the cellular actin structure was examined via immunofluorescence; we further investigated the molecular expressions of epithelial-mesenchymal transition (EMT) and the transforming growth factor-ß (TGF-ß) signaling pathways through Western blotting and RT-qPCR. These findings were substantiated through an in vivo nude mouse model of lung metastasis. We observed a decreased expression of CLIP170 in PTC in contrast to normal thyroid tissue. Functionally, the knockdown of CLIP170 (CLIP170KD) notably enhanced the metastatic potential and EMT of PTC cells, both in vitro and in vivo. Mechanistically, CLIP170KD triggered the activation of the TGF-ß pathway, subsequently promoting tumor cell migration, invasion, and EMT. Remarkably, the TGF-ß inhibitor LY2157299 effectively countered TGF-ß activity and significantly reversed tumor metastasis and EMT induced by CLIP170 knockdown. In summary, these findings collectively propose CLIP170 as a promising therapeutic target to mitigate metastatic tendencies in PTC.

Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer.

Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.

Blocking the angiopoietin-2-dependent integrin ß-1 signaling axis abrogates small cell lung cancer invasion and metastasis.

Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. Most patients are diagnosed at an extensive stage. However, the molecular mechanisms driving SCLC invasion and metastasis remain largely elusive. We used an autochthonous SCLC mouse model and matched samples from patients with primary and metastatic SCLC to investigate the molecular characteristics of tumor metastasis. We demonstrate that tumor cell invasion and liver metastasis in SCLC are triggered by an Angiopoietin-2 (ANG-2)/Integrin ß-1-dependent pathway in tumor cells, mediated by focal adhesion kinase/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin ß-1 or blocking Integrin ß-1 signaling by an anti-ANG-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched samples from patients with primary and metastatic SCLC confirmed a strong increase of Integrin ß-1 in liver metastasis in comparison with the primary tumor. We further show that ANG-2 blockade combined with PD-1-targeted by anti-PD-1 treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of ANG-2/Integrin ß-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a potentially new effective treatment strategy for patients with SCLC.

[Inaugural Scalp Metastasis of Pulmonary Squamous Cell Carcinoma: 
A Rare Case Report and Literature Review].

Distant cutaneous metastasis of primary lung squamous cell carcinoma is an exceedingly rare event, with scalp metastasis as the initial clinical presentation even rarer. Scalp skin metastases are prone to be misdiagnosed as other scalp disorders, yet their appearance signifies the deterioration and poor prognosis of lung cancer. This case report documents a female patient presenting initially with scalp folliculitis in dermatology, who was subsequently diagnosed with malignant lung tumor through radiological imaging and referred to Department of Thoracic Surgery. Pathological examination of the excised lesion from the scalp revealed distant metastasis of lung cancer. A review of similar cases reported in literature was conducted. This article aims to enhance understanding and awareness of skin metastasis in lung cancer, to emphasize the importance of this condition, and to improve early recognition and precise diagnosis. It is crucial to prevent clinical misdiagnosis and ensure appropriate treatment, finally leading to improve the prognosis of the patients.
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Patterns of distant metastasis and survival outcomes in de novo metastatic breast cancer according to age groups.

Background: Is de novo metastatic breast cancer (dnMBC) the same disease in the elderly as in younger breast cancer remains unclear. This study aimed to determine the metastatic patterns and survival outcomes in dnMBC according to age groups. Methods: We included patients from the Surveillance Epidemiology and End Results program. Chi-square test, multivariate logistic regression analyses, and multivariate Cox regression models were used for statistical analyses. Results: A total of 17719 patients were included. There were 3.6% (n=638), 18.6% (n=3290), 38.0% (n=6725), and 39.9% (n=7066) of patients aged <35, 35-49, 50-64, and ≥65 years, respectively. Older patients had a significantly higher risk of lung metastasis and a significantly lower risk of liver metastasis. There were 19.1%, 25.6%, 30.9%, and 35.7% of patients with lung metastasis in those aged <35, 35-49, 50-64, and ≥65 years, respectively. Moreover, the proportion of liver metastasis was 37.6%, 29.5%, 26.3%, and 19.2%, respectively. Age was the independent prognostic factor associated with breast cancer-specific survival (BCSS) and overall survival (OS). Those aged 50-64 years had significantly inferior BCSS (P<0.001) and OS (P<0.001) than those aged <35 years. Patients aged ≥65 years also had significantly lower BCSS (P<0.001) and OS (P<0.001) than those aged <35 years. However, similar outcomes were found between those aged 35-49 and <35 years. Conclusion: Our study suggests that different age groups may affect the metastatic patterns among patients with dnMBC and the survival of younger patients is more favorable than those of older patients.

The F-actin bundler SWAP-70 promotes tumor metastasis.

Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasis-related cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.

Laryngeal and oropharyngeal adenocarcinoma with pulmonary metastases in a common raven (Corvus corax).

A captive 15-year-old male common raven (Corvus corax) was presented for post-mortem examination. It had been previously presented to a local veterinarian due to a 3-4 weeks long history of abnormal respiratory sounds. Upon admission, the bird demonstrated severe dyspnea and a massive amount of mucous in the oropharynx. After symptomatic treatment, dyspnea deteriorated dramatically, and euthanasia was elicited because of poor prognosis. The necropsy revealed a 2.65 x 2.15 x 2.18 cm expansile and poorly delineated cauliflower-shaped mass around the glottis and extending inside the tracheal lumen. Additionally, a dilated salivary gland in the adjacent tissue and multifocal reddish-fleshy areas in the lung parenchyma were detected. Histopathological examination identified the mass as moderately differentiated, tubular adenocarcinoma with invasive growth and moderate to marked cellular atypia and numerous mitoses. The presumptive origin of the neoplasia was one of the salivary glands. Multiple metastases were identified in the lung both macroscopically and histologically. Bacterial culture and molecular testing for West Nile and Usutu viruses were negative. To the authors' knowledge, this is the first report of metastatic laryngeal and oropharyngeal adenocarcinoma in a common raven.

Case report: Sintilimab combined with anlotinib as neoadjuvant chemotherapy for metastatic bone tumor resection in patients with PSC.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC), which is resistant to chemotherapy and radiotherapy with a poor prognosis. PSC is highly malignant and is prone to recurrence even after surgery. The programmed death-ligand 1 (PD-L1) tumor cell proportion score (TPS) 5%, TERT and TP53 gene mutations were detected in this patient accompanied by multiple metastatic sites. The anlotinib is a novel multitarget tyrosine kinase inhibitor (TKI) that could be effective for advanced NSCLC and some sarcoma patients. Limited clinical trials and case reports have shown that PSC patients with gene mutations and PD-L1 expression have good responses to multitarget antiangiogenic drug and immune checkpoint inhibitors (ICIs). In this article, we reported a case with metastatic PSC diagnosed by Computed Tomography (CT)-guided needle biopsy treated with immunotherapy combined with antiangiogenic drugs as a neoadjuvant chemotherapy (NACT). PSC is controlled and the patient achieves successfully limb salvage treatment by surgical resection. Therefore, targeted therapy and immunotherapy can provide sufficient surgical opportunities for limb salvage in the treatment of metastatic PSC patients. Case summary: A 69-year-old male diagnosed with malignant bone tumor in the proximal femur was admitted to our hospital in June 2022 with recurrent fever as well as swelling and pain in the left thigh for twenty days. The initial computed tomography (CT) scan of the chest showed a pulmonary cavity (20 mm × 30 mm) and scattered lung masses. Subsequently, he underwent a CT-guided needle biopsy to distinguish the essence of osteolytic bone destruction and soft tissue mass in the left proximal femur which showed metastatic sarcomatoid carcinoma histology. Genetic testing revealed TERT c.-124C mutation (abundance 8.81%), TP53 p.R342 mutation (abundance 11.35%), tumor mutational burden (TMB) 7.09 muts/Mb, microsatellite stability (MSS), and PD-L1 (SP263) TPS 5% were also detected. The patient was tentatively treated with a combination of antiangiogenic drug and PD-1 inhibitor. After one course, the tumor volume significantly reduced in magnetic resonance imaging (MRI) and pathological fracture occurred in the femur after combined treatment. The patient received proximal femoral tumor resection and prosthesis replacement after defervescence. Sequentially sintilimab with anlotinib were administered for over 1 year. Finally, the local tumor was well controlled, and no obvious drug-related adverse reactions were observed. The lesions in the lung remained in partial response (PR) for more than 16 months and complete response (CR) of metastatic tumor in the proximal femur was observed through imaging examinations. Conclusion: This is the first reported case of a metastatic PSC in femur showing a favorable response to the treatment consisting of anlotinib combined with sintilimab. This case suggests that antiangiogenic therapy combined with immunotherapy may benefit patients with metastatic PSC in the preoperative adjuvant therapy for limb salvage.

SDF-1 promotes metastasis of NSCLC by enhancing chemoattraction of megakaryocytes through the PI3K/Akt signaling pathway.

Lung cancer (LC) is the leading cause of cancer-associated deaths worldwide, among which non-small-cell lung cancer (NSCLC) accounts for 80%. Stromal cell-derived factor-1 (SDF-1) inhibition results in a significant depletion of NSCLC metastasis. Additionally, SDF-1 is the only natural chemokine known to bind and activate the receptor CXCR4. Thus, we attempted to clarify the molecular mechanism of SDF-1 underlying NSCLC progression. Transwell migration, adhesion, and G-LISA assays were used to assess megakaryocytic chemotaxis in vitro and in vivo in terms of megakaryocytic migration, adherence, and RhoA activation, respectively. Western blotting was used to assess PI3K/Akt-associated protein abundances in MEG-01 cells and primary megakaryocytes under the indicated treatment. A hematology analyzer and flow cytometry were used to assess platelet counts in peripheral blood and newly formed platelet counts in Lewis LC mice under different treatments. Immunochemistry and flow cytometry were used to measure CD41+ megakaryocyte numbers in Lewis LC mouse tissue under different treatments. ELISA was used to measure serum TPO levels, and H&E staining was used to detect NSCLC metastasis.SDF-1 receptor knockdown suppressed megakaryocytic chemotaxis in Lewis LC mice. SDF-1 receptor inhibition suppressed megakaryocytic chemotaxis via the PI3K/Akt pathway. SDF-1 receptor knockdown suppressed CD41+ megakaryocyte numbers in vivo through PI3K/Akt signaling. SDF-1 receptor inhibition suppressed CD41+ megakaryocytes to hinder NSCLC metastasis. SDF-1 facilitates NSCLC metastasis by enhancing the chemoattraction of megakaryocytes via the PI3K/Akt signaling pathway, which may provide a potential new direction for seeking therapeutic plans for NSCLC.

[A Long-Surviving Case of Locally Advanced Breast Cancer with Multiple Lung Metastasis].

We report a case of right advanced breast cancer with multiple lung metastases in a 66-year-old woman. Her breast cancer( invasive ductal carcinoma, cT4bN1M1, Stage Ⅳ)was resected in October 2007(mastectomy plus axillary lymph node dissection)after local arterial infusion therapy(total dose 5-FU 4,735 mg plus adriamycin 180 mg), which caused bilateral lung arterial embolism due to deep vein thrombosis in right her leg. She had to be treated by anticoagulant therapy, mechanical ventilation and placement of IVC filter before her operation. Subsequent chemo-endocrine therapy(docetaxel 6 courses plus anastrozole)was continued. In October 2008, a CT scan showed disappearance of multiple lung metastases (complete response). In November 2015 (8 years after her operation), a CT scan showed recurrence of multiple lung metastases and endocrine therapy was changed to tamoxifen. A year later, a CT scan showed disappearance of multiple lung metastases(complete response)again and keep a condition of complete response in her breast cancer until May 2023 (15 years after her operation).

Brain radiotherapy and anlotinib control primary cardiac angiosarcoma with metastases: A case report.

RATIONALE: Primary cardiac angiosarcoma (PCA) is a rare and fatal disease with a poor prognosis. Whether the survival of PCA patients can be prolonged with additional treatment following complete surgical excision is controversial. PATIENT CONCERNS: In this case study, a 52-year-old male complained of chest tightness and pain for 7 days before admission into the hospital. Subsequently, he revisited the hospital because of dizziness and headache. DIAGNOSES: Initially, the patient was diagnosed with PCA in the right atrium by thoracic computed tomography (CT). Palliative resection identified brain, lung, and liver metastases. INTERVENTION: The patient accepted multimodal combination therapy, including first-line chemotherapy and then second-line anlotinib concurrent with brain radiotherapy and immunotherapy. OUTCOME: Although anlotinib combined with brain radiotherapy controlled the growth of intracranial lesions, progression-free survival (PFS) was only 5 months, and the overall survival (OS) was only 12 months. LESSON: The treatment for metastatic PCA needs an in-depth exploration.

Smad4 deficiency inhibits lung metastases through enhancing phagocytosis of lung interstitial macrophages.

Smad4, a critical mediator of TGF-ß signaling, plays a pivotal role in regulating various cellular functions, including immune responses. In this study, we investigated the impact of Smad4 knockout specifically in macrophages on anti-tumor immunity, focusing on lung metastasis of B16 melanoma cells. Using a mouse model with Smad4 knockout in macrophages established via Lyz2-cre mice and Smad4 flox/flox mice, we demonstrated a significant inhibition of B16 metastasis in the lungs. Interestingly, the inhibition of tumor growth was found to be independent of adaptive immunity, as no significant changes were observed in the numbers or activities of T cells, B cells, or NK cells. Instead, Smad4 knockout led to the emergence of an MCHIIlow CD206high subset of lung interstitial macrophages, characterized by enhanced phagocytosis function. Our findings highlight the crucial role of Smad4 in modulating the innate immune response against tumors and provide insights into potential therapeutic strategies targeting lung interstitial macrophages to enhance anti-tumor immunity.

Predictors of radioiodine (RAI)-avidity restoration for NTRK fusion-positive RAI-resistant metastatic thyroid cancers.

Context: Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported. Case presentation and results: We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of -0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. Conclusion: As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

Solitary Pulmonary Perivascular Epithelial Cell Tumor Mimicking Pulmonary Metastasis on 68 Ga-DOTATATE PET/CT in a Patient With Pancreatic Neuroendocrine Tumor.

ABSTRACT: We report the findings of 68 Ga-DOTATATE PET/CT in a 56-year-old woman with solitary pulmonary perivascular epithelioid cell tumor. 68 Ga-DOTATATE PET/CT showed a lesion with intense uptake in the region of pancreatic head and a solitary nodule with moderate uptake in the left lung. Pancreatic neuroendocrine tumor with pulmonary metastasis was considered. The postoperative pathological results showed a benign perivascular epithelioid cell tumor of the lung. This case emphasizes the need to increase awareness of benign perivascular epithelioid cell tumors in the differential diagnosis of solitary pulmonary nodule with moderate DOTATATE activity.

The incorporation of acetylated LAP-TGF-ß1 proteins into exosomes promotes TNBC cell dissemination in lung micro-metastasis.

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-ß1, the principal form of exosomal TGF-ß1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-ß signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-ß1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-ß1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-ß1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.