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Isolated pancreatic metastases (isPM) are a rare metastasizing pattern in the natural history of renal cell cancer. Their clinical hallmark is that they are confined to a single organ, the pancreas, while all other organs are unaffected for a long time. Almost all workers in the field suggested that mechanical tumor cell propagation to the pancreas may be the mechanism underlying this metastasizing pattern. In 2006 our group, by contrast, proposed an alternative mechanism, i.e. a special affinity of the tumor cells for the pancreas. In the present study an attempt was made to shed more light on the settlement of isPM by reviewing recent literature data. 666 observations of isPM reported in the literature were reviewed. The analyses showed that local lymphatic spread does not play a major role because the lymphatic system is, in general, rarely involved in isPM. This also applies to a local venous spread, because the site of pancreatic metastases is independent of the side affected by the primary renal cancer. But the results are compatible with a systemic metastatic pathway. That metastases in other organs, which would be expected given a systemic spread, are absent can plausibly be explained by a seed and soil mechanism: only the pancreas offers the tumor cell emboli an environment which is conducive to the growth of clinically manifest metastases, while settlement of metastatic tumor cells is prevented in all other organs.

Background A Sister Mary Joseph’s nodule is an umbilical metastasis from an intra-abdominal or pelvic malignancy, associated with a poor prognosis. Three possible metastatic pathways for Sister Mary Joseph’s nodule have been postulated: hematogenous spread, lymphatic dissemination, and direct invasion. However, detailed analyses of these metastatic pathways, particularly those involving gene expression profiling, are lacking in literature. We investigated the metastatic patterns of Sister Mary Joseph’s nodule by performing RNA microarray analysis of the primary tumor and each metastatic site in a case of fallopian tube cancer presenting with Sister Mary Joseph’s nodule and inguinal lymph node metastases. Case presentation A 48-year-old Japanese woman presented with swelling in an inguinal lymph node. Positron emission tomography-computed tomography imaging revealed multiple lymph node metastases, right ovarian tumor, umbilical metastasis, and peritoneal dissemination. The patient underwent a laparoscopic right adnexal resection, left inguinal lymph node biopsy, and umbilical resection. Pathological examination confirmed the diagnosis of primary high-grade serous carcinoma of the right fallopian tube. Metastatic high-grade serous carcinoma was identified in the lymph nodes and umbilical tissue. Tumor tissue samples were collected from the primary lesion, umbilical metastasis, and inguinal lymph node metastasis for RNA microarray analysis. The results showed that genes involved in cell adhesion, migration, and stromal remodeling associated with the metastatic processes were more highly expressed in both inguinal lymph node metastasis and Sister Mary Joseph’s nodule than in the primary lesion. Interestingly, distinct differences in gene expression profiles were observed between umbilical and lymph node metastases, suggesting different metastatic mechanisms. Conclusion Our findings suggest differences in the RNA expression patterns between Sister Mary Joseph’s nodule and lymph node metastases in fallopian tube cancer, indicating the possibility of distinct metastatic mechanisms. Further examination of similar cases and longitudinal studies are necessary to elucidate the metastatic patterns of Sister Mary Joseph’s nodule. This case highlights the potential value of molecular profiling for understanding the complex metastatic processes in gynecological malignancies.

Objectives Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. Methods A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. Results Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. Conclusions Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. Key points • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

The evidence for the existence of a heterogeneous population of cancer stem cells (CSCs) responsible for the initiation and maintenance of cancer has been characterized for several tumors recently. Purification and molecular characterization of normal human mammary stem cells from cultured mammospheres has been achieved, providing evidence supporting a model in which breast tumor heterogeneity is a reflection of a number of CSC-like cells in the tumor. A number of experimental methodologies have been developed to characterize epithelial stem cells, including the expression of cell surface or intracellular markers, mammosphere formation, exclusion of fluorescent dye by a side population, retention of the radionucleotide label, etc. Methodologies have also been successfully employed to identify tumorigenic cells within breast cancers. The most important characteristics of stem cells are the capacity for self-renewal and the regulation of the balance between self-renewal and differentiation. In the mammary gland, signaling pathways, such as Hedgehog (Hh), Wnt/β-catenin, and Notch, play a role in embryogenesis and organogenesis and maintenance of tissues in the adult through regulation of the balance between self-renewal and differentiation of stem cells. Breast TAAs include epitopes from proteins, such as carcinoembryonic antigen and NYBR-1, which are involved in tissue differentiation. Targeting BCSCs may be achieved by a number of approaches such as chemotherapy sensitization of BCSCs, differentiating therapy, targeting stem cell elimination, targeting signaling pathways and drug transporters, and inhibition of regulatory pathways involved in self-renewal. Targeting cells which have the potential to metastasize will be an important aspect of the BCSC field as these are the cells that cause the majority of morbidity and mortality from breast cancer.

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

Background Colorectal cancer (CRC) ranks as the second-leading cause of cancer-related death worldwide with metastases being the main cause of cancer-related death. Here, we investigated the genomic and transcriptomic alterations in matching adjacent normal tissues, primary tumors, and metastatic tumors of CRC patients. Methods We performed whole genome sequencing (WGS), multi-region whole exome sequencing (WES), simultaneous single-cell RNA-Seq, and single-cell targeted cDNA Sanger sequencing on matching adjacent normal tissues, primary tumors, and metastatic tumors from 12 metastatic colorectal cancer patients ( n =84 for genomes, n =81 for exomes, n =9120 for single cells). Patient-derived tumor organoids were used to estimate the anti-tumor effects of a PPAR inhibitor, and self-renewal and differentiation ability of stem cell-like tumor cells. Results We found that the PPAR signaling pathway was prevalently and aberrantly activated in CRC tumors. Blocking of PPAR pathway both suppressed the growth and promoted the apoptosis of CRC organoids in vitro, indicating that aberrant activation of the PPAR signaling pathway plays a critical role in CRC tumorigenesis. Using matched samples from the same patient, distinct origins of the metastasized tumors between lymph node and liver were revealed, which was further verified by both copy number variation and mitochondrial mutation profiles at single-cell resolution. By combining single-cell RNA-Seq and single-cell point mutation identification by targeted cDNA Sanger sequencing, we revealed important phenotypic differences between cancer cells with and without critical point mutations ( KRAS and TP53 ) in the same patient in vivo at single-cell resolution. Conclusions Our data provides deep insights into how driver mutations interfere with the transcriptomic state of cancer cells in vivo at a single-cell resolution. Our findings offer novel knowledge on metastatic mechanisms as well as potential markers and therapeutic targets for CRC diagnosis and therapy. The high-precision single-cell RNA-seq dataset of matched adjacent normal tissues, primary tumors, and metastases from CRCs may serve as a rich resource for further studies.

The Hippo pathway effector Yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ) play a critical role in promoting lung cancer progression, but paradoxically increase tumor cell sensitivity to ferroptosis, a form of lipid peroxidation‐driven cell death. The mechanism through which YAP/TAZ‐high cells evade ferroptosis during cancer progression remains unclear. Here, we showed that YAP/TAZ‐low lung cancer cells confer durable ferroptosis resistance to neighboring YAP/TAZ‐high cells through a non‐cell‐autonomous mechanism. Using murine lung carcinoma cell coculture models, we demonstrated that transient exposure to YAP/TAZ‐deficient cells induces a stable, contact‐independent ferroptosis‐resistant state in wild‐type (WT) cells, enhancing their metastatic seeding capacity in vivo. This adaptation is mediated by the upregulation of Gch1 , which encodes GTP cyclohydrolase 1 and suppresses ferroptosis via the synthesis of the antioxidant metabolite tetrahydrobiopterin (BH4). GCH1 overexpression alone was sufficient to confer ferroptosis resistance in WT cells, whereas conditioned medium from YAP/TAZ‐deficient cells replicated this effect, indicating that a soluble factor is involved in Gch1 induction. Importantly, the genetic deletion of Gch1 in YAP/TAZ‐deficient cells abolished their ability to protect WT cells, confirming its essential role in this intercellular program. Our findings revealed a Hippo pathway‐linked ferroptosis resistance mechanism and suggested that intra‐tumoral heterogeneity in YAP/TAZ activity promotes metastatic fitness by enabling the survival of ferroptosis‐prone cells via antioxidant signaling.

SummaryVantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological “hot spots” could improve the outcomes of PDAC immunotherapies.

Background We explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2 (HER2)‐positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway after trastuzumab treatment. Methods For this prospective multicenter clinical study, HER2‐positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022. Patients were randomly assigned to a trial or control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, while the control group patients received pyrotinib and chemotherapy. The RECIST v1.1 standard was used to evaluate efficacy. Descriptive statistics were used to summarize the clinicopathological features, and the Kaplan–Meier method was used to generate survival curves. The log‐rank test was used to compare progression‐free survival (PFS) between the two groups. Results A total of 59 HER2‐positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included, of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment. The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group, with no statistically significant difference (p = 0.507). The objective response rates were 27.3% for the inetetamab group and 29.4% for the pyrotinib group. The safety assessment indicated that the adverse event (AE) incidences were 86.1% (31/36) in the inetetamab group and 78.9 (15/19) in the pyrotinib group, with 9 (25%) and four (21.1%) Grade 3/4 AEs in the inetetamab and pyrotinib groups, respectively. Conclusions For metastatic HER2‐positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway‐activated metastatic HER2‐positive breast cancer patients. This prospective multicenter clinical study revealed that for metastatic Human epidermal factor receptor 2 (HER2)‐positive breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy, and this regimen could be one of the treatment options for PAM pathway activated metastatic HER2‐positive breast cancer patients.