Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism.

In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages

On the distribution of the trace elements V and Cr in an Al-Zn-Si alloy coating on a steel substrate

The Zn–55Al–1.6Si alloy is widely used in hot-dip galvanizing to coat steel and displays a multilayered microstructure (steel substrate/intermetallic compound (IMC) layer/coating overlay) that offers protection from corrosion. Trace level V and Cr are hypothesized to influence the corrosion performance of the coated steel via localized segregation. In this paper, the distribution of trace V and Cr is studied by using synchrotron X-ray fluorescence microscopy (XFM) and scanning transmission electron microscopy (STEM). It is revealed that V and Cr are both primarily segregated into the IMC layer and the top surface layer of the coating and are distributed continuously. The average concentrations for V and Cr are measured by XFM to be 7.7 ppm and 15.2 ppm in the IMC layer, and 4.6 ppm and 19.4 ppm on the top surface, respectively. STEM shows that the V distribution in the IMC layer is localized on the side adjacent to the coating overlayer. It is proposed that the IMC layer forms in two ways. One is the equilibrium phase transformation at 600 °C in the liquid Zn–55Al–1.6Si bath. The other way is the nonequilibrium phase transformation at the IMC/overlayer interface after V and Cr are rejected during solidification of the overlayer

Magnitude and distribution of cancer in a private teaching hospital, Bahir Dar, Ethiopia

# Background Cancer affects every country in the world irrespective of their developmental status. Since most studies have been performed primarily in public referral hospitals, this study aimed to describe the prevalence and histopathological patterns of cancer in a private setting. Cancer is one of the most common noncommunicable diseases, and regional variations in cancer incidence are responsible for the majority of deaths. The main objective of this study was to determine the magnitude and distribution of cancer among patients at GAMBY Teaching General Hospital. # Methods This retrospective study included a total of 4320 histopathological examination results recorded from January 1, 2016, to December 30, 2020. Descriptive statistics were used to present the results. The SPSS version 26 computer software package was used for data analysis. # Results A total of 4320 examinations revealed that 895 (20.7%) patients had confirmed malignancies. A total of 655 (73.2%) of the cases were females, with a male-to-female ratio of 1:2.73. The mean age of all the confirmed cases was 49.3±14.9 years. The age range was between 2 and 85 years. The mean ages of the females and males were 47.67±13.36 and 53.19±17.93 years, respectively. The most common cancers were cervical cancer (31.9%), breast cancer (12.7%), and skin cancer (11.6%). The top five cancers in the female patients were cervical, breast, nonmelanomatous skin, thyroid, and lymph node malignancies. Among male patients’ nonmelanomatous skin cancer, lymph node malignancies, colorectal cancer, bone and soft tissue cancer, and breast cancer constituted the top five cancers. Cancer involving the lung, eye and pancreas is the least common cancer. # Conclusions The results indicate that the pattern of cancer varies significantly from the global pattern of cancer distribution, as do studies in Africa and other regions of the country. The expansion of oncologic services, health education, screening and vaccination services, advancements in diagnostic modalities, and the involvement of the private sector in the management and care of cancer patients are very important health system focuses and forces policy makers to allocate resources accordingly. This study provided good insight into this pattern, but a wider multicenter survey and evaluation of sociodemographic and environmental factors are needed to assess the reasons for the variations

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Published online: 28 August 2023. OnlinePublThe lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.Jessica L. Chitty ... Australian Pancreatic Cancer Genome Initiative (APGI) (Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley) ... et al

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models